ClinVar Genomic variation as it relates to human health

The BRCA2 c.7090G>A variant is predicted to result in the amino acid substitution p.Glu2364Lys. This variant was reported in an individual with pancreatic cancer (Table S1, Hu et al. 2015. PubMed ID: 26483394). This variant was also documented in an affected individual and in a control from a large breast cancer cohort (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991; https://bcac.ccge.medschl.cam.ac.uk/bcacdata/bridges-summary-results-breast-cancer-risk-genes-2021). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32929080-G-A) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/52266/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces glutamic acid with lysine at codon 2364 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 an individual affected with pancreatic cancer (PMID: 26483394). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007111). This variant has been identified in 1/251006 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.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2364 of the BRCA2 protein (p.Glu2364Lys). This variant is present in population databases (rs80358940, gnomAD 0.0009%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 26483394). ClinVar contains an entry for this variant (Variation ID: 52266). 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.

The c.7090G>A (p.E2364K) alteration is located in exon 14 (coding exon 13) of the BRCA2 gene. This alteration results from a G to A substitution at nucleotide position 7090, causing the glutamic acid (E) at amino acid position 2364 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Variant summary: BRCA2 c.7090G>A (p.Glu2364Lys) results in a conservative amino acid change in the encoded protein sequence. Four of four 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 251006 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7090G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Hu_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. It has also been reported in Flossies in one European American individual. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.

Observed in individuals with pancreatic and breast cancer, but also in one unaffected control individual (Hu et al., 2016; Dorling et al., 2021); 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 7318G>A; This variant is associated with the following publications: (PMID: 26483394, 33471991, 29884841, 32377563)

This missense variant replaces glutamic acid with lysine at codon 2364 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 an individual affected with pancreatic cancer (PMID: 26483394). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007111). This variant has been identified in 1/251006 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.

Variant interpretted as Uncertain significance and reported on 07/03/2018 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Variant interpreted as Uncertain significance and reported on 07-03-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.