Submissions for variant NM_000059.4(BRCA2):c.7723A>G (p.Thr2575Ala)

dbSNP: rs1064793308

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482917	SCV000565720	uncertain significance	not provided	2017-02-22	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7723A>G at the cDNA level, p.Thr2575Ala (T2575A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Using alternate nomenclature, this variant would be defined as BRCA2 7951A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr2575Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr2575Ala occurs at a position that is not conserved and is located within the DNA binding domain (Yang 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Thr2575Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255592	SCV001432097	uncertain significance	not specified	2020-08-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7723A>G (p.Thr2575Ala) results in a non-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 251412 control chromosomes (gnomAD). 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.7723A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002402380	SCV002669919	likely benign	Hereditary cancer-predisposing syndrome	2020-02-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526519	SCV003009200	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2575 of the BRCA2 protein (p.Thr2575Ala). 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: 418575). 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.