ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2851T>C (p.Ser951Pro) (rs149522412)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129725 SCV000184530 benign Hereditary cancer-predisposing syndrome 2016-03-14 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;In silico models in agreement (benign)
GeneDx RCV000121763 SCV000211524 likely benign not specified 2018-02-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001030355 SCV000219017 benign Familial cancer of breast 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000129725 SCV000396083 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000397940 SCV000396084 uncertain significance Fanconi anemia, complementation group N 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589520 SCV000601773 likely benign not provided 2019-01-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121763 SCV000699578 likely benign not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2851T>C (p.Ser951Pro) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 283200 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. . In addition, the variant was reported in 8/2559 African American women (i.e. with a frequency of 0.0031), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.2851T>C has been reported in the literature in individuals affected with Breast Cancer, however, it was also found in controls (Zheng_2012, Haiman_2013, Wong-Brown_2014, Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (5x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589520 SCV000860568 uncertain significance not provided 2018-04-10 criteria provided, single submitter clinical testing
Color RCV000129725 SCV000902672 likely benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
ITMI RCV000121763 SCV000085961 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV001030355 SCV001193305 likely benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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