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

gnomAD frequency: 0.00006  dbSNP: rs200620434

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212784	SCV000149969	uncertain significance	not provided	2023-08-21	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, 33471991, 29522266, 27516001)
Invitae	RCV000114449	SCV000166636	likely benign	Familial cancer of breast	2024-02-01	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2023-08-02	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	2023-10-10	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 1.22 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. 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 it was 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 a 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. 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; six submitters classified the variant as benign or likely benign, while sevensubmitters classified it as a variant of uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000114449	SCV001140046	benign	Familial cancer of breast	2023-08-22	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
PreventionGenetics, part of Exact Sciences	RCV003415877	SCV004116062	uncertain significance	PALB2-related condition	2023-12-04	criteria provided, single submitter	clinical testing	The PALB2 c.1001A>G variant is predicted to result in the amino acid substitution p.Tyr334Cys. This variant has been reported in patients with hereditary breast, ovarian, or pancreatic cancers as well as in healthy controls (Catucci et al. 2014. PubMed ID: 24556926; Shindo et al. 2017. PubMed ID: 28767289; Balia et al. 2010. PubMed ID: 20852946). This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126581/). Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483471	SCV004228248	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-12	criteria provided, single submitter	curation	BP1, BP4, BS1?. According to the ACMG standard criteria we chose these criteria: BP1 (supporting benign): Coldspot region outside of functional important regions, BP4 (supporting benign): Aggregated score predicts a benign effect, BS1 (supporting benign): gnomAD nonCancer NFE AF: 0.0001080
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781695	SCV004242697	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
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