Submissions for variant NM_000465.4(BARD1):c.95G>T (p.Gly32Val)

gnomAD frequency: 0.00001  dbSNP: rs587782675

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132101	SCV000187166	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	The p.G32V variant (also known as c.95G>T), located in coding exon 1 of the BARD1 gene, results from a G to T substitution at nucleotide position 95. The glycine at codon 32 is replaced by valine, an amino acid with dissimilar properties. Functional analyses demonstrates that this alteration retains 87% homology-directed repair function compared to wild-type (Lee C et al. Hum. Mutat. 2015 Dec;36(12):1205-14). This variant has also been identified in 19/12503 unselected Japanese colorectal cancer patients and in 29/23705 controls. (Fujita M et al. Clin Gastroenterol Hepatol, 2020 Dec;:). This amino acid position is 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	RCV000542693	SCV000633076	uncertain significance	Familial cancer of breast	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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 142728). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 32 of the BARD1 protein (p.Gly32Val).
Counsyl	RCV000542693	SCV000786226	uncertain significance	Familial cancer of breast	2018-03-23	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030676	SCV001193504	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174898	SCV001338323	likely benign	not specified	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.95G>T (p.Gly32Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 236358 control chromosomes (gnomAD). However, the variant was reported at a frequency of 0.00067 (2.4 fold above the maximum pathogenic allele frequency) in a Japanese control population (jMorp) and in controls from a case-control study (Fujita_2022). To our knowledge, there are no reports of c.95G>T in individuals affected with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6014_6017delATAG, p.Asp2005ValfsX34; internal sample), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal homology-directed repair activity (Lee_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26350354, 30925164, 33309985). Five clinical diagnostic laboratories have submitted clinical-significance assessments (all uncertain significance) for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000132101	SCV001343716	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000542693	SCV004019283	uncertain significance	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000542693	SCV004217218	uncertain significance	Familial cancer of breast	2023-07-24	criteria provided, single submitter	clinical testing