VCV000051343.42 - ClinVar

NM_000059.4(BRCA2):c.2786T>C (p.Leu929Ser)

Germline

Top reviewed classifications are shown here.

Submission summary:

23 submissions

22 submitters

8 conditions

Reviewed by expert panel

Benign

Aug 2015 by Evidence-based…

for Breast-ovarian cancer, familial 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.2786T>C (p.Leu929Ser)

Variation ID: 51343 Accession: VCV000051343.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32337141 (GRCh38) [ NCBI UCSC ] 13: 32911278 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 1, 2014	Sep 29, 2024	Aug 10, 2015

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.2786T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Leu929Ser	missense
NC_000013.11:g.32337141T>C
NC_000013.10:g.32911278T>C
NG_012772.3:g.26662T>C
LRG_293:g.26662T>C
LRG_293t1:c.2786T>C	LRG_293p1:p.Leu929Ser
	NP_000050.2:p.Leu929Ser
U43746.1:n.3014T>C

... more HGVS ... less HGVS

Protein change

Other names

L929S
p.L929S:TTA>TCA
3014T>C

Canonical SPDI

NC_000013.11:32337140:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00200 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00376

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00377

The Genome Aggregation Database (gnomAD), exomes 0.00073

Exome Aggregation Consortium (ExAC) 0.00089

1000 Genomes Project 0.00200

1000 Genomes Project 30x 0.00234

The Genome Aggregation Database (gnomAD) 0.00355

Links

ClinGen: CA016363 dbSNP: rs2227943 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18995	19154

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast-ovarian cancer, familial, susceptibility to, 2	Benign (7)	reviewed by expert panel	Aug 10, 2015	RCV000077285.22
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000120345.32
Hereditary breast ovarian cancer syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000167848.25
Hereditary cancer-predisposing syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Aug 10, 2020	RCV000162622.14
Fanconi anemia complementation group D1	Likely benign (1)	criteria provided, single submitter	Feb 2, 2018	RCV000299643.13
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Jun 19, 2023	RCV000656593.22
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001353953.9
Breast and/or ovarian cancer	Benign (1)	criteria provided, single submitter	May 3, 2022	RCV003149672.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Aug 10, 2015)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000244432.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 21990134 Other databases http://hci-exlovd.hci.utah.edu/v… http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.2786T%3EC Comment: IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on … (more) IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000741 (less)
Benign (Nov 02, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805676.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018
Benign (Feb 17, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202280.7 First in ClinVar: Jan 29, 2015 Last updated: Sep 13, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Likely benign (Feb 02, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383657.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (5) PubMed: 21990134‚ 24323938‚ 15744044‚ 18284688‚ 18824701 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Feb 02, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group D1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383658.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Aug 10, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002535521.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Mar 04, 2014)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000494312.2 First in ClinVar: Feb 04, 2017 Last updated: Dec 11, 2022	Publications: PubMed (8) PubMed: 21990134‚ 20104584‚ 18824701‚ 18284688‚ 24323938‚ 16234499‚ 22034289‚ 15744044
Benign (May 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838149.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550308.4 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000072068.15 First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024
Benign (Nov 03, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Michigan Medical Genetics Laboratories, University of Michigan Accession: SCV000195970.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Tissue: Blood
Benign (Oct 08, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167346.11 First in ClinVar: Jun 23, 2014 Last updated: Aug 27, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Sep 30, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000683500.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Apr 29, 2014)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: literature only	Breast-ovarian cancer, familial 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220279.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 18824701‚ 21990134‚ 18284688‚ 15744044‚ 11030418
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016869.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Jun 19, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602853.6 First in ClinVar: Aug 27, 2017 Last updated: Feb 20, 2024
Benign (Nov 19, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000213057.6 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005236045.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (May 01, 2012)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000109082.5 First in ClinVar: Dec 23, 2013 Last updated: Sep 29, 2015
Benign (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000146107.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 9 Observation 2: Number of individuals with the variant: 1 Geographic origin: African American Observation 3: Number of individuals with the variant: 1 Geographic origin: Latin American, Caribbean Observation 4: Number of individuals with the variant: 21 Ethnicity/Population group: African Observation 5: Number of individuals with the variant: 3 Ethnicity/Population group: African American Observation 6: Number of individuals with the variant: 1 Ethnicity/Population group: African, Latin American, Caribbean Observation 7: Number of individuals with the variant: 2 Ethnicity/Population group: African, Native American Observation 8: Number of individuals with the variant: 1 Ethnicity/Population group: Trinidadian Observation 9: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, African, Native American Observation 10: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Jamaican (Africian), Scottish
Benign (Feb 28, 2018)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778655.1 First in ClinVar: Jun 25, 2018 Last updated: Jun 25, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591823.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Leu929Ser variant was identified in the BIC database 41X and in the UMD database and indicated as either having no clinical significance or as … (more) The p.Leu929Ser variant was identified in the BIC database 41X and in the UMD database and indicated as either having no clinical significance or as being neutral, respectively. This variant is not conserved in mammals and lower organisms, although computational analysis (SIFT, AlignGVGD, BLOSUM) disagree on whether or not this variant may impact the protein. However, this information is not informative. The variant was identified in the dbSNP database (ID: rs2227943) in the HapMap-Yoruban cohort with a frequency of 0.022 and in the exome variant server database as having with a frequency of 0.004 in the African American cohort, increasing the likelihood this variant does not have clinical significance. Furthermore, Myriad genetics calls this variant as a "polymorphism" increasing the likelihood this variant does not have clinical significance. In summary, this variant meets our laboratory's criteria to be classfied as benign. (less) Number of individuals with the variant: 3
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084497.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The p.Leu929Ser variant was identified in the BIC database 41X and in the UMD database and indicated as either having no clinical significance or as being neutral, respectively. This variant is not conserved in mammals and lower organisms, although computational analysis (SIFT, AlignGVGD, BLOSUM) disagree on whether or not this variant may impact the protein. However, this information is not informative. The variant was identified in the dbSNP database (ID: rs2227943) in the HapMap-Yoruban cohort with a frequency of 0.022 and in the exome variant server database as having with a frequency of 0.004 in the African American cohort, increasing the likelihood this variant does not have clinical significance. Furthermore, Myriad genetics calls this variant as a "polymorphism" increasing the likelihood this variant does not have clinical significance. In summary, this variant meets our laboratory's criteria to be classfied as benign.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Functional assays for analysis of variants of uncertain significance in BRCA2.	Guidugli L	Human mutation	2014	PMID: 24323938
High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients.	Fackenthal JD	International journal of cancer	2012	PMID: 22034289
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).	Lindor NM	Human mutation	2012	PMID: 21990134
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584
Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance.	Spearman AD	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18824701
Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients.	Lee E	Breast cancer research : BCR	2008	PMID: 18284688
Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry.	Nanda R	JAMA	2005	PMID: 16234499
Complete allelic analysis of BRCA1 and BRCA2 variants in young Nigerian breast cancer patients.	Fackenthal JD	Journal of medical genetics	2005	PMID: 15744044
Protein truncating BRCA1 and BRCA2 mutations in African women with pre-menopausal breast cancer.	Gao Q	Human genetics	2000	PMID: 11030418
The breast cancer information core: database design, structure, and scope.	Szabo C	Human mutation	2000	PMID: 10923033
http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.2786T%3EC	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
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Text-mined citations for rs2227943 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.2786T>C (p.Leu929Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2227943 ...