Submissions for variant NM_000059.4(BRCA2):c.8342A>G (p.Asn2781Ser)

dbSNP: rs1434821822

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001804319	SCV002052340	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2781 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 19656164) and in another individual affected with familial breast cancer with a pathogenic BRCA1 covariant (PMID: 28111427). 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.
Ambry Genetics	RCV001804319	SCV002676616	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-01	criteria provided, single submitter	clinical testing	The p.N2781S variant (also known as c.8342A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8342. The asparagine at codon 2781 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in cohorts of Korean breast cancer cases; however, at least one individual was also positive for a pathogenic mutation in the BRCA1 gene (Seong MW et al. Clin Genet, 2009 Aug;76:152-60; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541396	SCV002937099	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2781 of the BRCA2 protein (p.Asn2781Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 19656164, 28111427). ClinVar contains an entry for this variant (Variation ID: 1331803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Care Center, Daerim St. Mary`s Hospital	RCV002541396	SCV005423720	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-12	criteria provided, single submitter	clinical testing	The c.8342A>G variant in coding exon 19 of the BRCA2 gene results in a p.Asn2781Ser substitution. This position is highly conserved across most species (PMID: 19656164). This non-truncating nonsynonymous variant is located in an exonic hotspot and/or a critical functional domain of the gene. A different amino acid change at the same position (p.Asn2781Ile) has been reported as likely pathogenic in an ovarian cancer case (PMID: 18559594) and esophageal squamous cell cancer (PMID: 31396961). The c.8342A>G variant is not found in the gnomAD genomes and has an allele frequency of 0.004458% in the East Asian population of the gnomAD exomes database. Multiple computational prediction tools suggest a deleterious effect of this nonsynonymous missense variant on BRCA2 function. This variant was identified in three breast cancer patients: Patient 1 was diagnosed at the age of 50 and had a family history of breast cancer in her mother and sister, both diagnosed in their early 50s; Patient 2 was diagnosed with synchronous bilateral breast cancer at the age of 44; and Patient 3 was diagnosed with breast cancer at the age of 45. Additionally, this variant has been reported in other Korean breast cancer patients and families (PMID: 19656164, 28111427). Based on the available evidence, this variant is classified as likely pathogenic.