Submissions for variant NM_000465.4(BARD1):c.2291T>C (p.Ile764Thr)

gnomAD frequency: 0.00004  dbSNP: rs587780030

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115632	SCV000149541	uncertain significance	not provided	2023-03-20	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 breast cancer (Couch et al., 2015; Weber-Lassalle et al., 2019); This variant is associated with the following publications: (PMID: 25452441, 31036035, 36530327, 17550235, 33471991)
Invitae	RCV000466685	SCV000545655	uncertain significance	Familial cancer of breast	2024-01-19	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 764 of the BARD1 protein (p.Ile764Thr). This variant is present in population databases (rs587780030, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441, 31036035). ClinVar contains an entry for this variant (Variation ID: 127736). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Ambry Genetics	RCV000568015	SCV000660802	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.I764T variant (also known as c.2291T>C), located in coding exon 11 of the BARD1 gene, results from a T to C substitution at nucleotide position 2291. The isoleucine at codon 764 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). In another study, this alteration was detected in 1/4469 familial breast cancer patients as well as 2/37265 controls (Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000568015	SCV000682771	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 764 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual affected with breast cancer (PMID: 25452441, 31036035) and in a breast cancer case-control meta-analysis in 7/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000047). This variant has also been identified in 3/251226 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.
Mendelics	RCV000466685	SCV000837939	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	RCV001532967	SCV001748791	uncertain significance	not specified	2021-07-03	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.2291T>C (p.Ile764Thr) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) 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 1.2e-05 in 251226 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2291T>C has been reported in the literature in cases as well control individuals affected with Breast Cancer (example, Couch_2015, Weber-Lasalle_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115632	SCV002046139	uncertain significance	not provided	2021-06-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000466685	SCV002049518	uncertain significance	Familial cancer of breast	2021-04-19	criteria provided, single submitter	clinical testing	The BARD1 c.2291T>C; p.Ile764Thr variant (rs587780030) is reported in the literature in individuals affected with breast cancer (Couch 2014 and Weber-Lassalle 2018). This variant is also reported in ClinVar (Variation ID: 127736) and is found in the general population with an allele frequency of 0.0012% (3/251,226 alleles) in the Genome Aggregation Database. The isoleucine at codon 764 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.438). Due to limited information, the clinical significance of the p.Ile764Thr variant is uncertain at this time.
MGZ Medical Genetics Center	RCV000466685	SCV002579036	uncertain significance	Familial cancer of breast	2022-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415889	SCV004117495	uncertain significance	BARD1-related disorder	2023-08-14	criteria provided, single submitter	clinical testing	The BARD1 c.2291T>C variant is predicted to result in the amino acid substitution p.Ile764Thr. This variant has been reported in individuals with breast cancer (Supplementary Table 6, Couch et al. 2015. PubMed ID: 25452441; Table S4, Weber-Lassalle et al. 2019. PubMed ID: 31036035). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-215593443-A-G) and is reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127736/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000466685	SCV004217191	uncertain significance	Familial cancer of breast	2024-03-15	criteria provided, single submitter	clinical testing