ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.1379A>G (p.Gln460Arg) (rs749494645)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166836 SCV000217650 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166836 SCV000910808 likely benign Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing
GeneDx RCV000483813 SCV000565348 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.1379A>G at the cDNA level, p.Gln460Arg (Q460R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has been identified in individuals with breast and/or ovarian cancer and in an individual with familial prostate cancer (Hayano 2016, Nakagomi 2016, Decker 2017). PALB2 Gln460Arg was observed at an allele frequency of 0.10% (19/18,868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PALB2 Gln460Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000166836 SCV000396115 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000289282 SCV000396116 uncertain significance Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780567 SCV000917953 likely benign not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: PALB2 c.1379A>G (p.Gln460Arg) 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 of interest was observed with an allele frequency of 0.000069 in 276704 control chromosomes (gnomAD). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1379A>G, has been reported in the literature in individuals of East Asian descent affected with Hereditary Breast and Ovarian Cancer (Nakagomi_2016, Sato_2017). These report(s) do 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. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance" (3x) and "likely benign" (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000204210 SCV000259919 likely benign Familial cancer of breast 2017-12-18 criteria provided, single submitter clinical testing
Mendelics RCV000166836 SCV000839039 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000483813 SCV000807073 uncertain significance not provided 2017-08-02 criteria provided, single submitter clinical testing

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