Submissions for variant NM_000465.4(BARD1):c.97G>C (p.Ala33Pro)

gnomAD frequency: 0.00004  dbSNP: rs587782465

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131555	SCV000186557	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.A33P variant (also known as c.97G>C), located in coding exon 1 of the BARD1 gene, results from a G to C substitution at nucleotide position 97. The alanine at codon 33 is replaced by proline, an amino acid with highly similar properties. This alteration has been previously reported in 2/3236 individuals with invasive epithelial ovarian cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000235721	SCV000292491	uncertain significance	not provided	2022-05-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with epithelial ovarian cancer (Ramus et al., 2015); This variant is associated with the following publications: (PMID: 18480049, 26315354)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461802	SCV000545626	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 33 of the BARD1 protein (p.Ala33Pro). This variant is present in population databases (rs587782465, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 142436). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000131555	SCV000682828	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 33 of the BARD1 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 two individuals affected with ovarian cancer (PMID: 26315354). This variant has been identified in 9/268688 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582606	SCV001821419	uncertain significance	not specified	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.97G>C (p.Ala33Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 237324 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.97G>C has been reported in the literature as a non-deleterious variant in settings of multigene panel testing of BRIP1, BARD1, PALB2, and NBN in at-least two individuals affected with serous ovarian cancer (example, Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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.
Baylor Genetics	RCV000461802	SCV004217165	uncertain significance	Familial cancer of breast	2023-11-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000461802	SCV005405380	likely benign	Familial cancer of breast	2024-07-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
GenomeConnect - Invitae Patient Insights Network	RCV000461802	SCV001749738	not provided	Familial cancer of breast		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-06-2019 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.