Submissions for variant NM_000465.4(BARD1):c.1409A>G (p.Asn470Ser)

gnomAD frequency: 0.00008  dbSNP: rs587781976

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130369	SCV000185223	likely benign	Hereditary cancer-predisposing syndrome	2019-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000212130	SCV000209848	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Observed in individuals with BARD1-related and other cancers, but also in healthy controls (Ishitobi et al., 2003; De Brakeleer et al., 2010; Ramus et al., 2015; Ring et al., 2016; Arslan Ates et al., 2022; Maurer et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26738429, 15342711, 14550946, 20077502, 15855896, 19584272, 16633366, 23056176, 25980754, 27443514, 26315354, 27338793, 30374176, 34426522, 18480049, 26787654, 31371347, 35734982, 36187937, 35949786)
Invitae	RCV000197585	SCV000254570	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 470 of the BARD1 protein (p.Asn470Ser). This variant is present in population databases (rs587781976, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, endometrial cancer, ovarian cancer, and/or suspected Lynch syndrome (PMID: 14550946, 20077502, 25980754, 26315354). ClinVar contains an entry for this variant (Variation ID: 141739). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 18480049). 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	RCV000197585	SCV000786510	uncertain significance	Familial cancer of breast	2018-05-16	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000197585	SCV000886467	likely benign	Familial cancer of breast	2018-05-09	criteria provided, single submitter	research	The BARD1 variant designated as NM_000465.3:c.1409A>G (p.Asn470Ser) is classified as likely benign. This variant is listed in ClinVar (Variation ID: 141739) and has been classified as likely benign by another laboratory. The missense change resulting from this variant does not lead to structural defects in the protein (Fox et al, 2008, PMID: 18480049). Additionally, in one observed family, there are no BARD1-associated cancers reported for several individuals over age 50 who have or are at risk of having the variant. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BARD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Diagnostics, LLC DBA Color Health	RCV000130369	SCV000910696	likely benign	Hereditary cancer-predisposing syndrome	2015-11-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000197585	SCV001136187	benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212130	SCV001153292	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	BARD1: BP4, BP5, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174926	SCV001338367	likely benign	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1409A>G (p.Asn470Ser) results in a conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Additionally, Fox_2008 reports that this variant does not results in observable structural defects. The variant allele was found at a frequency of 0.00011 in 290022 control chromosomes, predominantly at a frequency of 0.00048 within the Finnish subpopulation in the gnomAD database and publications. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Breast Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.1409A>G has been reported in the literature in individuals affected with breast cancer, ovarian cancer or endometrial cancer as well as one individual who had a history of Lynch syndrome associated cancer and/or polyps, but has also been found in healthy controls (example, Ishitobi_2003, DeBrakeleer_2010, Yurgelun_2015, Ramus_2015, Young_2016, Ring_2016, Tsai_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least one co-occurrence with another pathogenic variant have been reported (APC c.220+2T>A, Tsai_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments benign/likely benign, n=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225431	SCV002505116	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197585	SCV004019241	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	RCV001174926	SCV004024301	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212130	SCV004221603	uncertain significance	not provided	2021-11-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 14550946 (2003), 26787654 (2016), 35734982 (2022), 33471991 (2021); see also LOVD (https://databases.lovd.nl/shared/)), endometrial/ovarian cancer (PMIDs: 27443514 (2016), 26315354 (2015)), and suspected Lynch syndrome (PMID: 25980754 (2015)). In addition, this variant has been observed in healthy control individuals (PMIDs: 20077502 (2010), 33471991 (2021)), and in an individual with colon cancer who co-carried a pathogenic variant in the APC gene (PMID: 30374176 (2019)). This variant has been reported to have no observable defects to the crystal structure of the BARD1 ankyrin repeat domain, however the effect of this variant on protein function and activity were not assessed (PMID: 18480049 (2008)). The frequency of this variant in the general population, 0.00048 (12/25110 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV002225431	SCV004231813	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	curation	Additional evidence agains pathogenicity from family/clinical data (see entries by Myriad and University of Washington). According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): CADD:15.07 REVEL: 0.17 BayesDEL:-0.584707, BS1 (supporting benign): gnomAD AF in FE