Submissions for variant NM_024675.4(PALB2):c.2438T>C (p.Ile813Thr)

gnomAD frequency: 0.00001  dbSNP: rs763191051

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476976	SCV000550675	uncertain significance	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 813 of the PALB2 protein (p.Ile813Thr). This variant is present in population databases (rs763191051, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 18446436, 35264596). ClinVar contains an entry for this variant (Variation ID: 410141). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000564912	SCV000663286	likely benign	Hereditary cancer-predisposing syndrome	2018-03-29	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588415	SCV000699566	uncertain significance	not provided	2017-08-09	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.2438T>C (p.Ile813Thr) variant located in the WD40/YVTN repeat-like-containing domain (via InterPro) involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 4/246270 control chromosomes at a frequency of 0.0000162, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). A publication cites the variant in two affected individuals, however, limited information is provided (ie, co-occurrence and/or cosegregation data). A clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588415	SCV000885885	likely benign	not provided	2017-07-27	criteria provided, single submitter	clinical testing	The PALB2 c.2438T>C;p.Ile813Thr variant has not been described in the medical literature or in gene-specific databases. The variant is listed in the ClinVar database (Variation ID: 410141) and the dbSNP variant database (rs763191051) with an allele frequency of 0.001624 percent (4/246270 alleles) in the Genome Aggregation Database. The isoleucine residue at this position is only partially conserved across species; amongst other mammalian species, 21 have isoleucine, 19 have threonine and 19 have another amino acid at this position. Furthermore, computational algorithms (AlignGVGD, SIFT, MutationTaster) all predict this variant is tolerated. Additionally, missense variants in PALB2 are not a known pathogenic mechanism for cancer predisposition (Tavtigian 2014, Tischkowitz 2012). Considering available information, this variant is classified as likely benign. References: Tavtigian SV and Chenevix-Trench G. Growing recognition of the role for rare missense substitutions in breast cancer susceptibility. Biomark Med. 2014;8(4):589-603. Tischkowitz M et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat. 2012 Apr;33(4):674-80.
Color Diagnostics, LLC DBA Color Health	RCV000564912	SCV000911949	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 813 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals or families affected with breast and/or ovarian cancer and it also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010897). This variant has been identified in 4/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV000476976	SCV001140008	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000476976	SCV004931403	likely benign	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
GeneDx	RCV000588415	SCV005078089	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18446436, 24485656, 28779002, 35264596)
PreventionGenetics, part of Exact Sciences	RCV004533194	SCV004717535	uncertain significance	PALB2-related disorder	2023-12-26	no assertion criteria provided	clinical testing	The PALB2 c.2438T>C variant is predicted to result in the amino acid substitution p.Ile813Thr. This variant has been reported in individuals with a personal or family history of breast cancer (Cao et al. 2008. PubMed ID: 18446436; Table S3, Guindalini et al 2022. PubMed ID: 35264596). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and interpreted as uncertain or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410141/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.