ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3479G>A (p.Arg1160Lys) (rs183920365)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210809 SCV000275029 likely benign Hereditary cancer-predisposing syndrome 2015-08-30 criteria provided, single submitter clinical testing
Color RCV000210809 SCV000903832 likely benign Hereditary cancer-predisposing syndrome 2017-03-07 criteria provided, single submitter clinical testing
Counsyl RCV000082913 SCV000785773 uncertain significance Breast-ovarian cancer, familial 2 2017-11-27 criteria provided, single submitter clinical testing
GeneDx RCV000521196 SCV000616971 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3479G>A at the cDNA level, p.Arg1160Lys (R1160K) 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 3707G>A. This variant has been reported in at least one individual with a personal and family history of breast cancer (Lara 2012). BRCA2 Arg1160Lys was observed at an allele frequency of 0.026% (3/11562) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg1160Lys occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Arg1160Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780007 SCV000916998 uncertain significance not specified 2017-12-06 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3479G>A (p.Arg1160Lys) variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 11/276602 control chromosomes (gnomAD), predominantly observed in the Latino subpopulation at a frequency of 0.000291 (10/34406). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). A publication, Poulet_2016, cites the variant with limited available information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases cite this variant with conflicting classifications, predominantly as "uncertain significance," and one as "likely benign. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000459507 SCV000549632 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1160 of the BRCA2 protein (p.Arg1160Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs183920365, ExAC 0.03%). This variant has been observed in an individual with a family history of breast and lung cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA2 which suggests that this c.3479G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 96792). 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.
Sharing Clinical Reports Project (SCRP) RCV000082913 SCV000114987 uncertain significance Breast-ovarian cancer, familial 2 2011-11-15 no assertion criteria provided clinical testing
Vantari Genetics RCV000210809 SCV000267015 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing

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