Submissions for variant NM_000465.4(BARD1):c.1360C>G (p.Pro454Ala)

gnomAD frequency: 0.00001  dbSNP: rs730881408

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212129	SCV000209827	uncertain significance	not provided	2023-12-28	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; Observed in individuals with endometrial or breast cancer (PMID: 27443514, 25186627); This variant is associated with the following publications: (PMID: 18480049, 25085752, 25186627, 38136308, 27443514)
Ambry Genetics	RCV000159802	SCV000215781	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	The p.P454A variant (also known as c.1360C>G), located in coding exon 5 of the BARD1 gene, results from a C to G substitution at nucleotide position 1360. The proline at codon 454 is replaced by alanine, an amino acid with highly similar properties. This variant has been reported in studies of individuals undergoing gene panel testing: in one study it was reported in a white, non-Ashkenazi Jewish female diagnosed with breast cancer at age 48 and, in another study, it was observed in a cohort of 381 unselected endometrial cancer patients (Tung N et al. Cancer. 2015 Jan;121:25-33; Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). 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	RCV000234332	SCV000284909	uncertain significance	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 454 of the BARD1 protein (p.Pro454Ala). This variant is present in population databases (rs730881408, gnomAD 0.0009%). This missense change has been observed in individual(s) with endometrial cancer or breast cancer (PMID: 25186627, 27443514). ClinVar contains an entry for this variant (Variation ID: 182033). 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.
Color Diagnostics, LLC DBA Color Health	RCV000159802	SCV000682687	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 454 of the BARD1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and endometrial cancer in the literature (PMID: 25186627, 27443514). This variant has been identified in 1/251328 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.
Counsyl	RCV000234332	SCV000785312	uncertain significance	Familial cancer of breast	2017-07-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000234332	SCV002814870	uncertain significance	Familial cancer of breast	2022-05-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114308	SCV003800771	uncertain significance	not specified	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1360C>G (p.Pro454Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251328 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1360C>G has been reported in the literature in individuals affected with Breast Cancer (Tung_2015) and Endometrial Cancer (Ring_2016) without evidence for causality. These reports 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000234332	SCV004019240	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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212129	SCV004221600	uncertain significance	not provided	2022-10-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251328 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with endometrial cancer (PMID: 27443514 (2016)) and in individuals with breast cancer (PMID: 25186627 (2015), 33471991 (2021), https://databases.lovd.nl/shared/variants/BARD1). 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.
Baylor Genetics	RCV000234332	SCV005054607	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing