Submissions for variant NM_000465.4(BARD1):c.1718T>C (p.Ile573Thr)

gnomAD frequency: 0.00001  dbSNP: rs587780022

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586551	SCV000149527	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, ovarian cancer, or neuroblastoma (PMID: 31036035, 27009842, 33552952); 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: 27878467, 33552952, 31036035, 31871109, 27009842, 32658311, 31159747, 17550235, 33471991, 35595798)
Ambry Genetics	RCV000115618	SCV000214163	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.I573T variant (also known as c.1718T>C), located in coding exon 8 of the BARD1 gene, results from a T to C substitution at nucleotide position 1718. The isoleucine at codon 573 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in a cohorts of individuals who underwent multi-gene panel testing for hereditary cancer (Yadav S et al. Fam Cancer, 2017 07;16:319-328; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Benito-Sánchez B et al. Sci Rep, 2022 May;12:8547) as well as an individual with neuroblastoma (Lasorsa VA et al. Oncotarget, 2016 Apr;7:21840-52). This variant has also been reported in large breast cancer cohorts but has also been identified in several healthy control individuals (Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367; Kadri MSN et al. Front Oncol, 2020 Jan;10:568786; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well 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	RCV000227623	SCV000284924	uncertain significance	Familial cancer of breast	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 573 of the BARD1 protein (p.Ile573Thr). This variant is present in population databases (rs587780022, gnomAD 0.005%). This missense change has been observed in individual(s) with neuroblastoma and/or personal or family history of breast and/or ovarian cancer (PMID: 27009842, 27878467, 31036035, 31871109, 32658311, 33552952, 35595798). ClinVar contains an entry for this variant (Variation ID: 127722). 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	RCV000115618	SCV000682726	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 573 of the BARD1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 33552952). In two case-control studies this variant has not shown an association with breast cancer (PMID: 31036035, 33471991). This variant has been identified in 7/282712 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420717	SCV000696757	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1718T>C (p.Ile573Thr) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251686 control chromosomes (gnomAD and Akcay_2020). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1718T>C has been reported in the literature in individuals with a personal or family history of breast or ovarian cancer (e.g., Yadav_2016, Adedokun_2020, Kadri_2021, Weber-Lasalle_2019, Benito-Sanchez_2022) as well as an individual affected with neuroblastoma (e.g., Lasorsa_2016). These reports however, 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. The following publications have been ascertained in the context of this evaluation (PMID: 31871109, 32658311, 35595798, 33552952, 27009842, 31036035, 27878467). Nine submitters have reported this variant to ClinVar after 2014 with conflicting interpretations (VUS, n = 8; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneKor MSA	RCV000115618	SCV000821890	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586551	SCV000888799	uncertain significance	not provided	2018-08-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115618	SCV002529544	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000227623	SCV004019753	likely benign	Familial cancer of breast	2023-04-03	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	RCV001420717	SCV004024844	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000227623	SCV004214974	uncertain significance	Familial cancer of breast	2023-10-08	criteria provided, single submitter	clinical testing