NM_000059.4(BRCA2):c.7954G>A (p.Val2652Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 9, 2024
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:: RCV000580117.10

Allele description [Variation Report for NM_000059.4(BRCA2):c.7954G>A (p.Val2652Met)]

NM_000059.4(BRCA2):c.7954G>A (p.Val2652Met)

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.7954G>A (p.Val2652Met)

HGVS:

NC_000013.11:g.32362671G>A
NG_012772.3:g.52192G>A
NM_000059.4:c.7954G>AMANE SELECT
NP_000050.2:p.Val2652Met
NP_000050.3:p.Val2652Met
LRG_293t1:c.7954G>A
LRG_293:g.52192G>A
LRG_293p1:p.Val2652Met
NC_000013.10:g.32936808G>A
NM_000059.3:c.7954G>A

Protein change:

V2652M

Links:

dbSNP: rs1466452770

NCBI 1000 Genomes Browser:

rs1466452770

Molecular consequence:

NM_000059.4:c.7954G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000683920	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 28, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005102196	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 9, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29394989, 29884841, 29988080, 34178674, 34597585 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000683920

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 28, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005102196

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 9, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

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

Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.

Guidugli L, Shimelis H, Masica DL, Pankratz VS, Lipton GB, Singh N, Hu C, Monteiro ANA, Lindor NM, Goldgar DE, Karchin R, Iversen ES, Couch FJ.

Am J Hum Genet. 2018 Feb 1;102(2):233-248. doi: 10.1016/j.ajhg.2017.12.013. Epub 2018 Jan 25.

PubMed [citation]

PMID:: 29394989
PMCID:: PMC5985401

See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000683920.3

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

#	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 Ambry Genetics, SCV005102196.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.V2652M variant (also known as c.7954G>A), located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7954. The valine at codon 2652 is replaced by methionine, an amino acid with highly similar properties. This alteration has been shown to be neutral in homology-directed DNA repair (HDR) assays (Hart SN et al. Genet. Med., 2019 01;21:71-80; Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This variant was found to be functionally intermediate in a BRCA2-null mouse embryonic stem cell complementation assay, a homology-directed repair assay, and a cisplatin sensitivity assay (Mesman RLS et al. Genet Med, 2019 Feb;21:293-302). This alteration was also classified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, and tumor pathology data (Caputo SM et al. Am J Hum Genet, 2021 Oct;108:1907-1923). This alteration was identified within a cohort of 874 unrelated Italian breast or ovarian cancer patients undergoing genetic testing based on suspicion for HBOC (Fanale D et al. Front Oncol, 2021 Jun;11:682445). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

#	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

Last Updated: Sep 29, 2024

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