Submissions for variant NM_024675.4(PALB2):c.1767G>A (p.Thr589=)

gnomAD frequency: 0.00002  dbSNP: rs769849072

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217926	SCV000273493	likely benign	Hereditary cancer-predisposing syndrome	2015-01-15	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.
GeneDx	RCV000436798	SCV000517332	benign	not specified	2015-06-25	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457514	SCV000550787	likely benign	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217926	SCV000690807	likely benign	Hereditary cancer-predisposing syndrome	2017-03-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121719	SCV001280365	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.
Sema4, Sema4	RCV000217926	SCV002530646	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000436798	SCV002760830	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002478785	SCV002774675	uncertain significance	not provided	2021-07-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436798	SCV004021218	likely benign	not specified	2023-06-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532777	SCV004118495	uncertain significance	PALB2-related disorder	2022-12-27	criteria provided, single submitter	clinical testing	The PALB2 c.1767G>A variant is not predicted to result in an amino acid change (p.=). This variant may create a cryptic splice site based on available splicing prediction programs (Alamut Visual Plus v1.6.1), however, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641708-C-T) and has conflicting interpretations in ClinVar ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/230075/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV002478785	SCV005075573	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BP7