ClinVar Genomic variation as it relates to human health

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 447 of the BARD1 protein (p.Leu447Val). This variant is present in population databases (rs376727038, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 26315354, 27878467, 31036035). ClinVar contains an entry for this variant (Variation ID: 182046). 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.

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].

In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 27878467 (2016), 26787654 (2016), 31036035 (2019), 33471991 (2021), and 35595798 (2022)) and metastatic prostate cancer (PMID: 32923906 (2020)), as well as healthy individuals (PMIDs: 26315354 (2015) and 33471991 (2021)). The frequency of this variant in the general population, 0.00015 (17/113638 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

PP3

This missense variant replaces leucine with valine at codon 447 of the BARD1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individual affected with breast cancer (PMID: 26787654, 31036035)m in an individual who fulfilled criteria to be tested for germline pathogenic mutations in BRCA1 and BRCA2 (PMID: 35595798), and in six unaffected individuals (PMID: 26315354, 31036035). In a large breast cancer case-control study, this variant has been observed in 18/60466 cases and 9/53461 controls (OR=1.769, 95%CI 0.794 to 3.937, p-value=0.18; Leiden Open Variation Database DB-ID BARD1_000256) (PMID: 33471991). This variant has also been identified in 19/251280 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.

The p.L447V variant (also known as c.1339C>G), located in coding exon 5 of the BARD1 gene, results from a C to G substitution at nucleotide position 1339. The leucine at codon 447 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in cancer cohorts including breast, ovarian, and metastatic prostate, as well as control individuals in several studies (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Yadav S et al. Fam Cancer, 2017 Jul;16:319-328; Young EL et al. J Med Genet, 2016 Jun;53:366-76; Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Boyle JL et al. JCO Precis Oncol, 2020 Mar;4:; Dorling et al. N Engl J Med 2021 02;384:428-439; Benito-Sánchez B et al. Sci Rep, 2022 May;12:8547). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: BARD1 c.1339C>G (p.Leu447Val) results in a conservative amino acid change located in the Ankyrin repeat (IPR002110) containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 1613400 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00016 vs 0.00025), allowing no conclusion about variant significance. c.1339C>G has been reported in the literature as a VUS in settings of multi-gene panel among individuals with breast and/or ovarian cancer and in unaffected controls (example, Young_2016, Ramus_2015, Yadav_2016, 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 co-occurrence with another pathogenic variant(s) has been observed at our laboratory (MLH1 c.546-1G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26315354, 26787654, 27878467, 31036035, 31371347). ClinVar contains an entry for this variant (Variation ID: 182046). Based on the evidence outlined above, the variant was classified as uncertain significance.

Observed in individuals with a personal history of breast cancer, at least one of whom also harbored a pathogenic BRCA2 variant, as well as in individuals with a history of sarcoma or prostate cancer, and in unaffected controls (PMID: 27498913, 31036035, 32726901, 32923906, 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26787654, 27878467, 26315354, 27498913, 31036035, 32726901, 32923906, 18480049, 33471991, 37418175, 35595798)