ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1763A>G (p.Asn588Ser) (rs373400041)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043876 SCV000071889 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 588 of the BRCA2 protein (p.Asn588Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 49 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs373400041, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 21735045, 20215541). This variant is also known as 1991A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 51186). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Studies have shown that this variant is associated with the activation of a cryptic splice site in exon 10 (PMID: 20215541, 21735045). 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.
CSER _CC_NCGL, University of Washington RCV000148439 SCV000190138 uncertain significance Breast neoplasm 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Ambry Genetics RCV000166539 SCV000217340 likely benign Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258376 SCV000326606 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166539 SCV000683445 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779918 SCV000916844 uncertain significance not specified 2019-04-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1763A>G (p.Asn588Ser) results in a 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5 donor site. These predictions have been confirmed by functional studies which show the variant creates a new cryptic donor site, which leads to an alternative transcript consisting of an in-frame deletion of 147 nucleotides (r.1763_1909del) that, in turn, produces an in-frame deletion of 49 amino acids with the insertion of a serine. However, due to the in-frame nature of this alternate splicing, it was considered a VUS (Menendez_2012, Sanz_2010). The variant allele was found at a frequency of 1.6e-05 in 249674 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1763A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018, Menendez_2012, Sanz_2010, Velasco_2005). One published study reports lack of co-segregation of the variant with the disease (affected mother did not carry the variant; Menendez_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported following internal testing (LabCorp; BRCA2 c.658_659delGT, p.Val220fsX4), providing supporting evidence for a benign role. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (1x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985469 SCV001133692 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262544 SCV001440462 uncertain significance Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing

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