Submissions for variant NM_000465.4(BARD1):c.2129A>T (p.Asp710Val)

gnomAD frequency: 0.00001  dbSNP: rs150121935

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131586	SCV000186597	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-18	criteria provided, single submitter	clinical testing	The p.D710V variant (also known as c.2129A>T), located in coding exon 11 of the BARD1 gene, results from an A to T substitution at nucleotide position 2129. The aspartic acid at codon 710 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is highly 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	RCV000198509	SCV000254576	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 710 of the BARD1 protein (p.Asp710Val). This variant is present in population databases (rs150121935, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 142456). 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. 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.
GeneDx	RCV001857462	SCV000293819	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Absent from cases but observed in controls in an ovarian cancer case-control study (PMID: 26315354); This variant is associated with the following publications: (PMID: 23056176, 17550235, 26315354)
Counsyl	RCV000198509	SCV000785194	uncertain significance	Familial cancer of breast	2017-05-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131586	SCV001359828	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 710 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 not been reported in individuals affected with hereditary cancer in the literature. In a large breast cancer case-control study, this variant was identified in 6/60460 cases, 6/53455 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID BARD1_000084). This variant has been identified in 2/251362 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	RCV000236887	SCV001361541	uncertain significance	not specified	2019-06-28	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.2129A>T (p.Asp710Val) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251362 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.2129A>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000198509	SCV004019277	likely benign	Familial cancer of breast	2023-02-24	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].
Baylor Genetics	RCV000198509	SCV004214951	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000198509	SCV004041692	uncertain significance	Familial cancer of breast	2023-10-09	no assertion criteria provided	clinical testing