Submissions for variant NM_024675.4(PALB2):c.12T>C (p.Pro4=)

gnomAD frequency: 0.00009  dbSNP: rs567706422

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123332	SCV000166642	likely benign	Familial cancer of breast	2025-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000212765	SCV000211499	benign	not specified	2014-08-01	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.
Ambry Genetics	RCV000160826	SCV000213259	likely benign	Hereditary cancer-predisposing syndrome	2014-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000123332	SCV000268038	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000160826	SCV000537495	likely benign	Hereditary cancer-predisposing syndrome	2015-08-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858740	SCV000604597	likely benign	not provided	2024-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212765	SCV000699528	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121824	SCV001280475	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.
Genetic Services Laboratory, University of Chicago	RCV000212765	SCV002067964	likely benign	not specified	2020-03-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160826	SCV002530601	likely benign	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000123332	SCV004019629	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212765	SCV004242707	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000123332	SCV000487924	likely benign	Familial cancer of breast	2015-12-04	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000858740	SCV001549130	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Pro4= variant was not identified in the literature nor was it identified in the LOVD 3.0. The variant was identified in dbSNP (ID: rs567706422) as "With other allele", and ClinVar (classified as benign by GeneDx; as likely benign by six submitters; as uncertain significance by Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 16 of 273234 chromosomes at a frequency of 0.000059 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23578 chromosomes (freq: 0.000042), Other in 1 of 6400 chromosomes (freq: 0.00016), European in 14 of 124134 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro4= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.