2-214809475-C-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The ENST00000260947.9(BARD1):c.95G>T(p.Gly32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G32S) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000260947.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.95G>T | p.Gly32Val | missense_variant | 1/11 | ENST00000260947.9 | NP_000456.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.95G>T | p.Gly32Val | missense_variant | 1/11 | 1 | NM_000465.4 | ENSP00000260947 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1457692Hom.: 0 Cov.: 76 AF XY: 0.0000138 AC XY: 10AN XY: 725100
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 24, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 27, 2023 | 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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 24, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 23, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 23, 2019 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at