ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3419G>A (p.Ser1140Asn) (rs80358585)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589884 SCV000694695 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3419G>A (p.Ser1140Asn) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Ser1140 is not located in a known functional domain of the Breast cancer type 2 susceptibility protein, and an Asn residue can be found at this position in both chicken and mouse, suggesting that this substitution is tolerated. This variant was absent in 121090 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications and/or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000704802 SCV000833769 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1140 of the BRCA2 protein (p.Ser1140Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with breast cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.3419G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 495452). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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.

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