Submissions for variant NM_000059.4(BRCA2):c.6966G>T (p.Met2322Ile)

gnomAD frequency: 0.00001  dbSNP: rs80358924

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255458	SCV000296532	uncertain significance	not provided	2020-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000255458	SCV000321479	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7194G>T; Observed in individuals with breast cancer (Cochran et al., 2014; Caminsky et al., 2016); This variant is associated with the following publications: (PMID: 24824029, 26898890)
Ambry Genetics	RCV000509983	SCV000608122	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	The p.M2322I variant (also known as c.6966G>T), located in coding exon 12 of the BRCA2 gene, results from a G to T substitution at nucleotide position 6966. The methionine at codon 2322 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in multiple breast cancer patients (Cochran RL et al. Hum. Pathol., 2014 Jul;45:1546-50; Caminsky NG et al. Hum. Mutat., 2016 07;37:640-52). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001337745	SCV001531358	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-27	criteria provided, single submitter	clinical testing	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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 52229). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24824029, 26898890). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2322 of the BRCA2 protein (p.Met2322Ile).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804773	SCV002051074	uncertain significance	not specified	2021-12-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6966G>T (p.Met2322Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250028 control chromosomes. c.6966G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Cochran_2014, Caminsky_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Sema4, Sema4	RCV000509983	SCV002536287	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-21	criteria provided, single submitter	curation
Baylor Genetics	RCV003460604	SCV004216059	uncertain significance	Familial cancer of breast	2023-06-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509983	SCV004362185	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 2322 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 reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 24824029, 26898890). This variant has been identified in 1/250028 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.
All of Us Research Program, National Institutes of Health	RCV000077391	SCV004844335	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 2322 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 reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 24824029, 26898890). This variant has been identified in 1/250028 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)	RCV000077391	SCV000109188	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077391	SCV000146983	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing