VCV000136539.17 - ClinVar

NM_007294.4(BRCA1):c.671-8A>G

Interpretation:: Conflicting interpretations of pathogenicity
Uncertain significance(3); Benign(4); Likely benign(1)
Review status:: criteria provided, conflicting interpretations
Submissions:: 10
First in ClinVar:: Apr 4, 2014
Most recent Submission:: Dec 11, 2022
Last evaluated:: Jan 6, 2022
Accession:: VCV000136539.17
Variation ID:: 136539
Description:: single nucleotide variant

NM_007294.4(BRCA1):c.671-8A>G

Allele ID

140242

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

17q21.31

Genomic location

17: 43094868 (GRCh38) GRCh38 UCSC

17: 41246885 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_007294.4:c.671-8A>G MANE Select
NM_007297.4:c.530-8A>G
NM_007298.3:c.671-8A>G
NM_007299.4:c.671-8A>G
NM_007300.4:c.671-8A>G
NC_000017.11:g.43094868T>C
NC_000017.10:g.41246885T>C
NG_005905.2:g.123116A>G
LRG_292:g.123116A>G
LRG_292t1:c.671-8A>G
U14680.1:n.790-8A>G

... more HGVS ... less HGVS

Protein change

Other names

IVS10-8A>G

Canonical SPDI

NC_000017.11:43094867:T:C

Functional consequence

Global minor allele frequency (GMAF)

0.00020 (C)

Allele frequency

The Genome Aggregation Database (gnomAD) 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00009

Exome Aggregation Consortium (ExAC) 0.00012

The Genome Aggregation Database (gnomAD), exomes 0.00008

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

1000 Genomes Project 0.00020

Links

Breast Cancer Information Core (BIC) (BRCA1): 790-8&base_change=A to G

ClinGen: CA003807

dbSNP: rs80358144

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Breast-ovarian cancer, familial, susceptibility to, 1	Uncertain significance	3	criteria provided, multiple submitters, no conflicts	Jun 23, 2017	RCV000112769.5
Hereditary cancer-predisposing syndrome	Benign/Likely benign	2	criteria provided, multiple submitters, no conflicts	Jan 6, 2022	RCV000580371.4
not provided	Benign	2	criteria provided, single submitter	Mar 26, 2016	RCV000588347.5
Hereditary breast ovarian cancer syndrome	Benign	1	criteria provided, single submitter	Dec 8, 2021	RCV001087483.6
not specified	Conflicting interpretations of pathogenicity	2	criteria provided, conflicting interpretations	Apr 12, 2019	RCV000123888.6

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
BRCA1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	13277	13461

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Benign (Mar 26, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699288.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (1) PubMed: 16267036 Comment: Variant Summary: The c.671-8A>G variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. This variant is located at a position that … (more) Variant Summary: The c.671-8A>G variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. This variant is located at a position that is not widely known to affect splicing, 3/5 splicing prediction programs via Alamut predict no significant effect on splicing, and mutation taster predicts the variant to be a polymorphism. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.012%, predominantly observed in the East Asian subpopulation at a frequency of 0.18%. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.10%), suggesting this is a benign polymorphism found primarily in population(s) of East Asian origin. The variant has been reported in multiple databases to co-occur in individuals with pathogenic BRCA1 variants including two patients with c.2296_2297delAG, p.Ser766X (UMD), one patient with c.68_69delAG, p.Glu23ValfsX17 (UMD), and one patient with c.188T>A, p.Leu63Ter (BIC). Taken together, the multiple co-occurrences with pathogenic variants along with the intronic nature of the variant and the relatively high frequency in the East Asian population, this variant was classified as Benign. (less)
Uncertain significance (May 04, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services,Illumina Accession: SCV001284087.1 First in ClinVar: May 31, 2020 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory,University of Chicago Accession: SCV002072426.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Dec 08, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Invitae Accession: SCV000252822.8 First in ClinVar: Oct 11, 2015 Last updated: May 16, 2022
Likely benign (Jan 06, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4,Sema4 Accession: SCV002537887.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Publications: PubMed (2) PubMed: 28480178‚ 32467295
Benign (Oct 12, 2016)	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: SCV000683345.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Dec 30, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167233.11 First in ClinVar: Jun 20, 2014 Last updated: Feb 24, 2015	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)
Uncertain significance (Jun 23, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785272.2 First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014	Publications: PubMed (4) PubMed: 28364669‚ 28111427‚ 16267036‚ 28480178
Uncertain significance (Feb 20, 2004)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 1 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA1) Accession: SCV000145661.1 First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014	Number of individuals with the variant: 3 Ethnicity/Population group: Asian
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001552352.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Number of individuals with the variant: 1

Comment:

Variant Summary: The c.671-8A>G variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. This variant is located at a position that is not widely known to affect splicing, 3/5 splicing prediction programs via Alamut predict no significant effect on splicing, and mutation taster predicts the variant to be a polymorphism. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.012%, predominantly observed in the East Asian subpopulation at a frequency of 0.18%. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.10%), suggesting this is a benign polymorphism found primarily in population(s) of East Asian origin. The variant has been reported in multiple databases to co-occur in individuals with pathogenic BRCA1 variants including two patients with c.2296_2297delAG, p.Ser766X (UMD), one patient with c.68_69delAG, p.Glu23ValfsX17 (UMD), and one patient with c.188T>A, p.Leu63Ter (BIC). Taken together, the multiple co-occurrences with pathogenic variants along with the intronic nature of the variant and the relatively high frequency in the East Asian population, this variant was classified as 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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.

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:

Citations for this variant

Title	Author	Journal	Year	Link
Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population.	Dong H	Journal of medical genetics	2021	PMID: 32467295
Next-generation sequencing of BRCA1/2 in breast cancer patients: potential effects on clinical decision-making using rapid, high-accuracy genetic results.	Park HS	Annals of surgical treatment and research	2017	PMID: 28480178
Suggestion of BRCA1 c.5339T>C (p.L1780P) variant confer from 'unknown significance' to 'Likely pathogenic' based on clinical evidence in Korea.	Ryu JM	Breast (Edinburgh, Scotland)	2017	PMID: 28364669
Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls.	Park JS	Cancer research and treatment	2017	PMID: 28111427
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.	Judkins T	Cancer research	2005	PMID: 16267036

Text-mined citations for rs80358144...

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 Jan 21, 2023

ClinVar Genomic variation as it relates to human health

NM_007294.4(BRCA1):c.671-8A>G

NM_007294.4(BRCA1):c.671-8A>G

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs80358144...