NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 2, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000113685.14

Allele description [Variation Report for NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu)]

NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.7007G>T (p.Arg2336Leu)

Other names:

7235G>T

HGVS:

NC_000013.11:g.32346896G>T
NG_012772.3:g.36417G>T
NM_000059.4:c.7007G>TMANE SELECT
NP_000050.2:p.Arg2336Leu
NP_000050.3:p.Arg2336Leu
LRG_293t1:c.7007G>T
LRG_293:g.36417G>T
LRG_293p1:p.Arg2336Leu
NC_000013.10:g.32921033G>T
NM_000059.3:c.7007G>T
U43746.1:n.7235G>T

Protein change:

R2336L

Links:

Breast Cancer Information Core (BIC) (BRCA2): 7235&base_change=G to T; dbSNP: rs28897743

NCBI 1000 Genomes Browser:

rs28897743

Molecular consequence:

NM_000059.4:c.7007G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000146993	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (Feb 20, 2013)	germline, somatic	clinical testing
SCV000327567	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016)	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV001434898	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 5, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004844346	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Oct 2, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 22970155, 27157322, 28993434, 30078507, 31565484, 31742824, 31782247, 35886069, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	not provided	108544	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Chinese	somatic	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis.

Kwong A, Ng EK, Wong CL, Law FB, Au T, Wong HN, Kurian AW, West DW, Ford JM, Ma ES.

PLoS One. 2012;7(9):e43994. doi: 10.1371/journal.pone.0043994. Epub 2012 Sep 7.

PubMed [citation]

PMID:: 22970155
PMCID:: PMC3436879

Detection of Germline Mutation in Hereditary Breast and/or Ovarian Cancers by Next-Generation Sequencing on a Four-Gene Panel.

Kwong A, Shin VY, Au CH, Law FB, Ho DN, Ip BK, Wong AT, Lau SS, To RM, Choy G, Ford JM, Ma ES, Chan TL.

J Mol Diagn. 2016 Jul;18(4):580-94. doi: 10.1016/j.jmoldx.2016.03.005. Epub 2016 May 5.

PubMed [citation]

PMID:: 27157322

See all PubMed Citations (9)

Details of each submission

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146993.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	not provided
2	Chinese	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	somatic	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000327567.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	1	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434898.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This c.7007G>T (p.Arg2336Leu) variant in exon 13 of the BRCA2 gene is the last base of exon 13 and is predicted to alter splicing resulting in a frame shift. This variant has been reported in patients with breast cancer (PMID: 22970155) and is not observed in general population databases. Other nucleotide base substitutions at this same site have also been observed to alter splicing and are considered pathogenic (PMID: 18489799, 9150172). Therefore, the c.7007G>T (p.Arg2336Leu) variant in the BRCA2 gene is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004844346.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces arginine with leucine at codon 2336 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant also changes the last nucleotide of exon 13 of the BRCA2 gene and splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies for this variant, different variants affecting the same splice donor site (c.7007G>A, c.7007G>C) have been shown to produce aberrant RNA transcripts and are considered to be disease-causing (ClinVar variation ID: 38077, 52241). It suggests that the reference sequence at this splice site is important for normal RNA splicing. This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 22970155, 27157322, 28993434, 30078507, 31742824, 31782247, 35886069, Color internal data) and non-small cell lung cancer (PMID: 31565484). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 9, 2024

ClinVar

Relating variation to medicine