ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1508A>G (p.Lys503Arg) (rs62625304)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195388 SCV000075515 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 503 of the BRCA1 protein (p.Lys503Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs62625304, ExAC 0.003%). This variant has been observed in an individual affected with ovarian cancer (PMID: 22711857). ClinVar contains an entry for this variant (Variation ID: 54274). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000132145 SCV000187216 likely benign Hereditary cancer-predisposing syndrome 2017-12-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Conflicting evidence
GeneDx RCV000047502 SCV000210103 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1508A>G at the cDNA level, p.Lys503Arg (K503R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant, also known as 1627A>G using alternate nomenclature, was observed in at least one individual with ovarian cancer (Alsop 2012). BRCA1 Lys503Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Lys503Arg is located in the NLS1 within the DNA binding domain and in a region known to interact with multiple other proteins (Narod 2004, Borg 2010, Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Lys503Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000111633 SCV000785209 uncertain significance Breast-ovarian cancer, familial 1 2017-06-02 criteria provided, single submitter clinical testing
Color RCV000132145 SCV000909379 likely benign Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780972 SCV000918673 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1508A>G (p.Lys503Arg) variant involves the alteration of a non-conserved nucleotide located in the BRCA1 nuclear localization signal 1 (NLS1) (Fabbro 2002). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). One study based on evolutionary comparative analyses predicted a benign role of the variant (Burk-Herrick 2005), although functional studies have not confirmed this prediction. This variant was found in 3/245882 control chromosomes (gnomAD) at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant was observed in at least one individual with ovarian cancer (Alsop 2012) and also has been reported in affected individual(s) from HBOC families (Judkins 2005), however limited information was provided (i.e. no co-segregation data were included) so the causal link between the variant and disease could not be independently validated. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until additional information becomes available.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111633 SCV000144115 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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