ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.659T>C (p.Leu220Ser) (rs138593305)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131224 SCV000186177 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing The p.L220S variant (also known as c.659T>C), located in coding exon 4 of the BARD1 gene, results from a T to C substitution at nucleotide position 659. The leucine at codon 220 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was observed in 2/3236 cases with invasive epithelial ovarian cancer and 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). In another study, this variant was identified in a patient with breast and/or ovarian cancer, who had a positive family history and had negative BRCA1/2 genetic testing (Syeda MM et al. Genet. Med. 2017 Sep;19:1071-1077). 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.
GeneDx RCV000585398 SCV000209841 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.659T>C at the cDNA level, p.Leu220Ser (L220S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant was identified in 2/3,236 cases and 1/3,431 controls in an ovarian cancer case-control study (Ramus 2015), as well as in a pediatric glioma patient (Zhang 2015). BARD1 Leu220Ser was observed at an allele frequency of 0.02% (21/120654) in individuals of European ancestry in large population cohorts (Lek 2016). Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Leu220Ser is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BARD1 Leu220Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205881 SCV000259944 uncertain significance Familial cancer of breast 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 220 of the BARD1 protein (p.Leu220Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs138593305, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with breast and/or ovarian cancer, as well as in healthy controls (PMID: 26315354, 28301456). Additionally, this variant has also been reported in an individual affected with high-grade glioma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 142225). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C5. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. 5
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585398 SCV000693039 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855575 SCV000696780 uncertain significance not specified 2019-04-18 criteria provided, single submitter clinical testing Variant summary: BARD1 c.659T>C (p.Leu220Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 270932 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (9.2e-05 vs 0.00025), allowing no conclusion about variant significance. c.659T>C has been reported in the literature in individuals affected with Ovarian Cancer or glioma (Ramus_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585398 SCV000887600 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131224 SCV000902724 likely benign Hereditary cancer-predisposing syndrome 2015-10-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000205881 SCV001296631 uncertain significance Familial cancer of breast 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357448 SCV001552925 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Leu220Ser variant was identified in 2 of 6748 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Ramus 2015). The variant was also identified in dbSNP (ID: rs138593305 as "With Uncertain significance allele"), ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, and two other clinical laboratories), MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic database. The variant was identified in control databases in 22 of 257210 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 21 of 120654 chromosomes (freq: 0.0002) and Ashkenazi Jewish in 1 of 8898 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. The p.Leu220 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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