Submissions for variant NM_000059.4(BRCA2):c.3966C>G (p.Asn1322Lys)

gnomAD frequency: 0.00001  dbSNP: rs80358647

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572841	SCV000666147	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-13	criteria provided, single submitter	clinical testing	The p.N1322K variant (also known as c.3966C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3966. The asparagine at codon 1322 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759607	SCV000889033	uncertain significance	not provided	2024-11-26	criteria provided, single submitter	clinical testing	The BRCA2 c.3966C>G (p.Asn1322Lys) variant has been identified in the published literature in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). A multifactorial probability analysis study has reported that this variant is likely benign (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.0000088 (2/228428 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781155	SCV000919027	uncertain significance	not specified	2018-11-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3966C>G (p.Asn1322Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-06 in 224534 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3966C>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000572841	SCV001339317	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1322 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported with posterior probability of being pathogenic of 0.0075 based on family history likelihood of 0.3457 from two carrier families (PMID: 31131967). This variant has been identified in 2/228428 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001306019	SCV001495374	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000572841	SCV003848565	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Myriad Genetics, Inc.	RCV000077317	SCV004186063	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV004803172	SCV004845249	uncertain significance	BRCA2-related cancer predisposition	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1322 of the BRCA2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported with posterior probability of being pathogenic of 0.0075 based on family history likelihood of 0.3457 from two carrier families (PMID: 31131967). This variant has been identified in 2/228428 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.
Sharing Clinical Reports Project (SCRP)	RCV000077317	SCV000109114	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-04-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077317	SCV000146348	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing