Submissions for variant NM_024675.4(PALB2):c.734C>T (p.Ala245Val)

gnomAD frequency: 0.00001  dbSNP: rs571063157

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130900	SCV000185809	likely benign	Hereditary cancer-predisposing syndrome	2017-03-20	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200032	SCV000255112	uncertain significance	Familial cancer of breast	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 245 of the PALB2 protein (p.Ala245Val). This variant is present in population databases (rs571063157, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 142078). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
GeneDx	RCV000483902	SCV000567564	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25186949, 19369211)
Counsyl	RCV000200032	SCV000785605	uncertain significance	Familial cancer of breast	2017-10-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130900	SCV000904039	likely benign	Hereditary cancer-predisposing syndrome	2017-04-28	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315412	SCV004015181	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 245 of the PALB2 protein (p.Ala245Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs571063157, ExAC 0.02%). This variant has not been reported in the literature in individuals with PALB2-related disease. ClinVar contains an entry for this variant (Variation ID: 142078). In-silico predictions show benign computational verdict based on 12 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no pathogenic predictions and the position is not highly conserved. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Myriad Genetics, Inc.	RCV000200032	SCV004019701	uncertain significance	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130900	SCV004228007	benign	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483902	SCV005623242	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	The PALB2 c.734C>T (p.Ala245Val) variant has been reported in the published literature in individuals with breast cancer (PMID: 33309985 (2020), 30287823 (2018), 28779002 (2017)), and in reportedly healthy individuals (PMID: 33309985 (2020), 31214711 (2020)). The frequency of this variant in the general population, 0.00016 (5/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001030168	SCV005727212	uncertain significance	not specified	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.734C>T (p.Ala245Val) 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 1.3e-05 in 1614114 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.3e-05 vs 0.00016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.734C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 142078). Based on the evidence outlined above, the variant was classified as uncertain significance.
Leiden Open Variation Database	RCV001030168	SCV001193007	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.