16-23629680-C-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_024675.4(PALB2):āc.2474G>Cā(p.Arg825Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R825G) has been classified as Likely benign.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2474G>C | p.Arg825Thr | missense_variant | 5/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2474G>C | p.Arg825Thr | missense_variant | 5/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251430Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135906
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727248
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 12, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2020 | This variant is associated with the following publications: (PMID: 28580595, 26692951) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 16, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2020 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 19, 2020 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2021 | Variant summary: PALB2 c.2474G>C (p.Arg825Thr) 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 0.00016 in 251430 control chromosomes, predominantly at a frequency of 0.0022 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 14.079 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 East Asian origin. c.2474G>C has been reported in the literature in individuals affected with various types of cancers includin leiomyosarcoma, stomach adenocarcinoma, breast cancer and urothelial carcinoma, all without strong evidence for causality (Yang_2015, Lu_2015, Kwong_2020, Xie_2018, Yang_2021). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; four classified as VUS while four classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Endometrial carcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ACT Genomics, | Jul 20, 2020 | The allele frequency of this variant c.2474G>C (p.Arg825Thr) is 0.0037 in East Asian of gnomAD and 0.004 in East Asian of 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between arginine and threonine. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at