NM_000059.4(BRCA2):c.7942A>C (p.Ser2648Arg) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004012386.2

Allele description [Variation Report for NM_000059.4(BRCA2):c.7942A>C (p.Ser2648Arg)]

NM_000059.4(BRCA2):c.7942A>C (p.Ser2648Arg)

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.7942A>C (p.Ser2648Arg)

HGVS:

NC_000013.11:g.32362659A>C
NG_012772.3:g.52180A>C
NM_000059.4:c.7942A>CMANE SELECT
NM_001406719.1:c.7846A>C
NM_001406720.1:c.7942A>C
NM_001406721.1:c.3010A>C
NM_001406722.1:c.1525A>C
NP_000050.2:p.Ser2648Arg
NP_000050.3:p.Ser2648Arg
NP_001393648.1:p.Ser2616Arg
NP_001393649.1:p.Ser2648Arg
NP_001393650.1:p.Ser1004Arg
NP_001393651.1:p.Ser509Arg
LRG_293t1:c.7942A>C
LRG_293:g.52180A>C
LRG_293p1:p.Ser2648Arg
NC_000013.10:g.32936796A>C
NM_000059.3:c.7942A>C
NR_176251.1:n.8141A>C

Protein change:

S1004R

Molecular consequence:

NM_000059.4:c.7942A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406719.1:c.7846A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406720.1:c.7942A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406721.1:c.3010A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406722.1:c.1525A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_176251.1:n.8141A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004833462	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jul 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35190686, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004833462

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jul 10, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Saturation variant interpretation using CRISPR prime editing.

Erwood S, Bily TMI, Lequyer J, Yan J, Gulati N, Brewer RA, Zhou L, Pelletier L, Ivakine EA, Cohn RD.

Nat Biotechnol. 2022 Jun;40(6):885-895. doi: 10.1038/s41587-021-01201-1. Epub 2022 Feb 21.

PubMed [citation]

PMID:: 35190686

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004833462.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces serine with arginine at codon 2648 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to be functional in a haploidized cell proliferation assay (PMID: 35190686). To our knowledge, this variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Sep 1, 2024

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