Submissions for variant NM_000465.4(BARD1):c.1568T>C (p.Val523Ala)

gnomAD frequency: 0.00005  dbSNP: rs587780017

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589446	SCV000149521	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate 60% homology-directed repair function compared to wildtype (Adamovich et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, colon, prostate, and other cancers (Mandelker et al., 2017; Yurgelun et al., 2017; Isaacsson Velho et al., 2018; Bhai et al., 2021); This variant is associated with the following publications: (PMID: 28135145, 29368341, 26496030, 27878467, 28873162, 31036035, 18480049, 30925164, 34326862, 36845387)
Ambry Genetics	RCV000115612	SCV000186582	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The p.V523A variant (also known as c.1568T>C), located in coding exon 6 of the BARD1 gene, results from a T to C substitution at nucleotide position 1568. The valine at codon 523 is replaced by alanine, an amino acid with similar properties. This alteration was seen in a cohort of unselected patients with colorectal cancer and in a patient who previously tested negative for mutations in BRCA1 and BRCA2 (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095; Yadav S et al. Fam. Cancer. 2017 07;16(3):319-328). This amino acid position is highly 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.
Invitae	RCV001079586	SCV000254571	likely benign	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115612	SCV000537517	likely benign	Hereditary cancer-predisposing syndrome	2020-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000722111	SCV000696747	likely benign	not specified	2022-08-18	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1568T>C (p.Val523Ala) results in a non-conservative amino acid change located in the ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Four of four computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.8e-05 in 256674 control chromosomes (gnomAD and Weber-Lassalle_2019). This frequency is not significantly higher than expected for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.8e-05 vs 0.00025), allowing no conclusion about variant significance. The variant has also been found in three individuals in the FLOSSIES database (a cohort of African American and European American women over 70 years of age who have never had cancer). c.1568T>C has been reported in the literature as a VUS in settings of multigene testing in one individual affected with breast cancer, one individual with colorectal cancer, and one with prostate cancer (e.g. Yadav 2016, Yurgelun 2017, Isaacsson Velho_2018) and also in an individual from a control population (Weber-Lassalle_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The variant protein was not found to have a significant impact on homology directed repair activity compared to wild-type BARD1 (e.g. Adamovich_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with conflicting assessments (likely benign n=3; VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001079586	SCV001301849	uncertain significance	Familial cancer of breast	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sema4, Sema4	RCV000115612	SCV002527021	likely benign	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation