ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.971G>A (p.Arg324Lys) (rs397507435)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129650 SCV000184448 likely benign Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000589361 SCV000278837 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.971G>A at the cDNA level, p.Arg324Lys (R324K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 1199G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg324Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg324Lys occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Arg324Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000409872 SCV000488877 uncertain significance Breast-ovarian cancer, familial 2 2016-07-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589361 SCV000600875 uncertain significance not provided 2019-04-27 criteria provided, single submitter clinical testing
Color RCV000129650 SCV000689220 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000216915 SCV000695264 uncertain significance not specified 2019-03-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.971G>A (p.Arg324Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 228110 control chromosomes (genomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Tung_2015). The report does 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000637477 SCV000758937 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-01-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 324 of the BRCA2 protein (p.Arg324Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs397507435, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 141234). 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 lysine 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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