Submissions for variant NM_000059.4(BRCA2):c.7349A>T (p.Asn2450Ile)

gnomAD frequency: 0.00001  dbSNP: rs761505767

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773097	SCV000906552	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 2450 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 3/251124 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	RCV000804173	SCV000944069	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-11	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 2450 of the BRCA2 protein (p.Asn2450Ile). This variant is present in population databases (rs761505767, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 252844). 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 with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000773097	SCV001188659	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	The p.N2450I variant (also known as c.7349A>T), located in coding exon 13 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7349. The asparagine at codon 2450 is replaced by isoleucine, an amino acid with dissimilar 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265710	SCV002547741	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7349A>T (p.Asn2450Ile) 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 1.2e-05 in 251124 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.7349A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000238922	SCV004844398	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 2450 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 3/251124 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.
Baylor Genetics	RCV004567797	SCV005059149	uncertain significance	Familial cancer of breast	2023-12-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000238922	SCV000297447	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-07	no assertion criteria provided	clinical testing