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NM_000059.4(BRCA2):c.7447A>G (p.Ser2483Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 27, 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:
RCV000164907.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.7447A>G (p.Ser2483Gly)]

NM_000059.4(BRCA2):c.7447A>G (p.Ser2483Gly)

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.7447A>G (p.Ser2483Gly)
HGVS:
  • NC_000013.11:g.32356439A>G
  • NG_012772.3:g.45960A>G
  • NM_000059.4:c.7447A>GMANE SELECT
  • NP_000050.2:p.Ser2483Gly
  • NP_000050.3:p.Ser2483Gly
  • LRG_293t1:c.7447A>G
  • LRG_293:g.45960A>G
  • LRG_293p1:p.Ser2483Gly
  • NC_000013.10:g.32930576A>G
  • NM_000059.3:c.7447A>G
  • U43746.1:n.7675A>G
  • p.S2483G
Protein change:
S2483G
Links:
dbSNP: rs80358966
NCBI 1000 Genomes Browser:
rs80358966
Molecular consequence:
  • NM_000059.4:c.7447A>G - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000215595Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(May 23, 2022) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV001359212Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 27, 2023) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.

Karchin R, Agarwal M, Sali A, Couch F, Beattie MS.

Cancer Inform. 2008;6:203-16. Epub 2008 Apr 18.

PubMed [citation]
PMID:
19043619
PMCID:
PMC2587343

Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer.

Montalban G, Bonache S, Moles-Fernández A, Gisbert-Beamud A, Tenés A, Bach V, Carrasco E, López-Fernández A, Stjepanovic N, Balmaña J, Diez O, Gutiérrez-Enríquez S.

J Med Genet. 2019 Feb;56(2):63-74. doi: 10.1136/jmedgenet-2018-105606. Epub 2018 Nov 24.

PubMed [citation]
PMID:
30472649
See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000215595.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.S2483G variant (also known as c.7447A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7447. The serine at codon 2483 is replaced by glycine, an amino acid with similar properties. This variant has been reported in high risk breast cancer families and a high risk breast and ovarian cancer family (Osorio A et al. Int. J. Cancer. 2002 May;99:305-9; Weber F et al. Am. J. Hum. Genet. 2006 Jun;78:961-72; Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12). One study found that this alteration results in incomplete use of this cryptic acceptor site, producing a transcript with the predicted in-frame deletion of 12 nucleotides in coding exon 14 (Fraile-Bethencourt E et al. Front Genet. 2019 May;10:503). However, other studies have found that this alteration does not result in a significant amount of aberrant splicing (Ambry internal data, Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92). This amino acid position is poorly conserved in available vertebrate species. In addition, this amino acid change is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV001359212.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This missense variant replaces serine with glycine at codon 2483 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). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). A RNA study reported that this variant resulted in 10% of transcripts with an in-frame partial deletion of exon 15 (resulting in the protein change Asp2479_Ser2483delinsGly). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11979449, 12955716, 16685647, 21735045), an individual with breast/ovarian cancer or Lynch syndrome (PMID: 32522261) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000190). This variant has been identified in 4/251306 chromosomes 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024