Submissions for variant NM_024675.4(PALB2):c.2851T>C (p.Ser951Pro)

gnomAD frequency: 0.00058  dbSNP: rs149522412

Total submissions: 19

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	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000589520	SCV000211524	likely benign	not provided	2021-09-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28779002, 23824750, 24728327, 23555315, 21932393)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001030355	SCV000219017	benign	Familial cancer of breast	2025-02-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000129725	SCV000396083	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	2022-10-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Eurofins Ntd Llc (ga)	RCV000589520	SCV000860568	uncertain significance	not provided	2018-04-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129725	SCV000902672	likely benign	Hereditary cancer-predisposing syndrome	2015-01-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589520	SCV002010964	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589520	SCV002048252	likely benign	not provided	2021-08-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129725	SCV002530731	likely benign	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121763	SCV002551645	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589520	SCV004033462	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: BP4
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129725	SCV004228022	benign	Hereditary cancer-predisposing syndrome	2023-11-14	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589520	SCV001978540	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589520	SCV001979392	likely benign	not provided		no assertion criteria provided	clinical testing