Submissions for variant NM_000059.4(BRCA2):c.8342A>T (p.Asn2781Ile)

dbSNP: rs1434821822

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637364	SCV000758820	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2781 of the BRCA2 protein (p.Asn2781Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 18559594, 31396961). This variant is also known as 8570A>T. ClinVar contains an entry for this variant (Variation ID: 531223). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841, 33609447). 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.
Color Diagnostics, LLC DBA Color Health	RCV000772450	SCV000905628	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine 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). A functional study has reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID: 29884841, 33609447). This variant has been reported in an individual affected with ovarian cancer (PMID: 18559594). A multifactorial analysis also has reported a family history likelihood ratio for pathogenicity of 0.3667 (PMID: 31131967). 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	RCV000772450	SCV001178682	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-18	criteria provided, single submitter	clinical testing	The p.N2781I variant (also known as c.8342A>T), located in coding exon 18 of the BRCA2 gene, results from an A to T substitution at nucleotide position 8342. The asparagine at codon 2781 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was identified in an individual with ovarian cancer (Soegaard M et al. Clin. Cancer Res. 2008 Jun;14:3761-7). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Based on internal structural analysis, N2781I is more destabilizing to the local structure of the OB1 domain in BRCA2 than other pathogenic variants (Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477402	SCV002774264	likely pathogenic	not provided	2021-06-18	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org) and has been reported in individuals with breast ovarian cancer and esophageal squamous cell cancer in the published literature (PMID: 18559594 (2008), 31396961 (2020)). Recent functional studies reports that this variant has a deleterious effect on BRCA2 homologous directed repair (HDR) activity (PMID: 29884841 (2019), 33609447 (2021)). Based on the available information, this variant is classified as likely pathogenic.
Baylor Genetics	RCV004568401	SCV005059162	uncertain significance	Familial cancer of breast	2023-12-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802309	SCV005425792	uncertain significance	BRCA2-related cancer predisposition	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine 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). A functional study has reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID: 29884841, 33609447). This variant has been reported in an individual affected with ovarian cancer (PMID: 18559594). A multifactorial analysis also has reported a family history likelihood ratio for pathogenicity of 0.3667 (PMID: 31131967). 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV004808815	SCV005431457	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-06-27	criteria provided, single submitter	clinical testing	The following ACMG criteria is used: PM2_Supporting (not reported in gnomAD), PS3 (PMID: 38417439); PP3 (BayesDel 0.4161)