Submissions for variant NM_000465.4(BARD1):c.1339C>G (p.Leu447Val)

gnomAD frequency: 0.00008  dbSNP: rs376727038

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656772	SCV000209846	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000159815	SCV000215700	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230416	SCV000284908	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000230416	SCV000489657	uncertain significance	Familial cancer of breast	2016-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159815	SCV000537520	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656772	SCV000600175	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000230416	SCV000837965	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212127	SCV000918620	uncertain significance	not specified	2024-03-26	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000159815	SCV002527001	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000230416	SCV004019239	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212127	SCV004024854	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000230416	SCV004214969	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656772	SCV004225981	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing	PP3