Submissions for variant NM_000059.4(BRCA2):c.7739A>G (p.Gln2580Arg)

gnomAD frequency: 0.00001  dbSNP: rs1064795508

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480812	SCV000571384	uncertain significance	not provided	2018-06-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7739A>G at the cDNA level, p.Gln2580Arg (Q2580R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 7967A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Gln2580Arg was not observed in large population cohorts (Lek 2016). Since BRCA2 Gln2580Arg is located within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Gln2580Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573542	SCV000668749	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	The p.Q2580R variant (also known as c.7739A>G), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7739. The glutamine at codon 2580 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637758	SCV000759235	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2580 of the BRCA2 protein (p.Gln2580Arg). This variant is not present in population databases (gnomAD no frequency). 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: 422026). 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.
Color Diagnostics, LLC DBA Color Health	RCV000573542	SCV000910439	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2580 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230517	SCV003928497	uncertain significance	not specified	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7739A>G (p.Gln2580Arg) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain ( IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251416 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.7739A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and 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	RCV004003368	SCV004844460	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2580 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 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535437	SCV001749340	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-15-2016 by GeneDx. 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.