Submissions for variant NM_000465.4(BARD1):c.1247T>G (p.Leu416Arg)

gnomAD frequency: 0.00003  dbSNP: rs878853996

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227805	SCV000284904	uncertain significance	Familial cancer of breast	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 416 of the BARD1 protein (p.Leu416Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteosarcoma or hepatoblastoma (PMID: 26580448, 35264596, 35495172, 36187937). ClinVar contains an entry for this variant (Variation ID: 237815). 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 tolerated. 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	RCV000564518	SCV000660827	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	clinical testing	The c.1247T>G (p.L416R) alteration is located in exon 4 (coding exon 4) of the BARD1 gene. This alteration results from a T to G substitution at nucleotide position 1247, causing the leucine (L) at amino acid position 416 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mendelics	RCV000227805	SCV000837968	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564518	SCV000911680	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 416 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 reported for this variant. This variant has been reported in an individual affected with osteosacroma (PMID: 26580448). This variant has not been identified 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	RCV001553565	SCV001774461	uncertain significance	not specified	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1247T>G (p.Leu416Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1247T>G has been reported in the literature in an individual affected with Osteosacroma (Zhang_2015). This report however, does 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001566238	SCV001789726	uncertain significance	not provided	2023-10-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35495172, 36187937, 35264596, 26580448)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000227805	SCV002512238	uncertain significance	Familial cancer of breast	2021-05-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate, BP4 supporting
Sema4, Sema4	RCV000564518	SCV002526996	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001566238	SCV004221599	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022)), osteosarcoma (PMID: 26580448 (2015)), and hepatoblastoma (PMID: 35495172 (2022)). The frequency of this variant in the general population, 0.00026 (4/15278 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843497	SCV002103147	likely pathogenic	Hepatoblastoma		no assertion criteria provided	research