ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1001A>G (p.Tyr334Cys)

gnomAD frequency: 0.00006  dbSNP: rs200620434
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212784 SCV000149969 uncertain significance not provided 2022-03-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27363283, 28767289, 22692731, 21618343, 22241545, 25186627, 26483394, 20852946, 24556926, 26315354, 27150160, 28779002, 32659497, 30374176, 29300386, 33134171)
Invitae RCV000114449 SCV000166636 likely benign Familial cancer of breast 2021-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116060 SCV000185244 likely benign Hereditary cancer-predisposing syndrome 2020-06-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study
University of Washington Department of Laboratory Medicine,University of Washington RCV000114449 SCV000611877 benign Familial cancer of breast 2018-03-28 criteria provided, single submitter research The PALB2 variant designated as NM_024675.3:c.1001A>G (p.Tyr334Cys) is classified as benign. This variant is present in 1 in 2200 individuals with European ancestry (exac.broadinstitute.org). It is classified as likely benign in the LOVD PALB2 database (https://databases.lovd.nl/shared/variants/PALB2 curated by Tischowitz & Auerbach). Computer programs predict that this variant is likely to be tolerated. This genomic position is not highly conserved. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <0.1% probability of pathogenicity, which is consistent with a classification of benign. This variant is not predicted to alter PALB2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212784 SCV000889566 likely benign not provided 2020-06-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116060 SCV000910665 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781695 SCV000919951 likely benign not specified 2021-08-02 criteria provided, single submitter clinical testing Variant summary: PALB2 c.1001A>G (p.Tyr334Cys) results in a non-conservative amino acid change in 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 0.00012 in 253494 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 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 Non-Finnish European origin. Moreover, the variant was also found in 7/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). c.1001A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Balia 2010, Catucci 2014, Catucci 2012, Tischkowitz 2012, Tung 2014, Hellebrand 2011), and other tumor phenotypes (e.g. Shindo 2017, Grazel_2020), but were also found in healthy controls (e.g. Balia 2010, Catucci 2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.942+3A>T), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments but with an emerging consensus leaning towards a benign/likely (n=5) outcome (VUS, n=5). Based on the evidence outlined above, the variant was re-classified as likely benign.
Mendelics RCV000114449 SCV001140046 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000114449 SCV001370405 uncertain significance Familial cancer of breast 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798290 SCV002043579 uncertain significance Breast and/or ovarian cancer 2020-12-21 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000781695 SCV002066737 uncertain significance not specified 2020-12-30 criteria provided, single submitter clinical testing DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.1001A>G, in exon 4 that results in an amino acid change, p.Tyr334Cys. This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European sub-population (dbSNP rs200620434). Also reported as c.1201A>G in the literature, this sequence change has been reported in a family with breast and/or ovarian cancer (PMID: 20852946). The p.Tyr334Cys change affects a poorly conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. The p.Tyr334Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Tyr334Cys change remains unknown at this time.
Sema4,Sema4 RCV000116060 SCV002530575 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-28 criteria provided, single submitter curation
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415191 SCV000492602 uncertain significance Hereditary cancer 2016-04-13 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000114449 SCV001193051 uncertain significance Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000212784 SCV002037053 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000212784 SCV002037250 uncertain significance not provided no assertion criteria provided clinical testing

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