rs587780820
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The ENST00000261584.9(PALB2):c.2087C>T(p.Thr696Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,892 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. T696A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000261584.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2087C>T | p.Thr696Met | missense_variant | 5/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2087C>T | p.Thr696Met | missense_variant | 5/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | Aug 25, 2018 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of breast or prostate, as well as in control groups (Nguyen-Dumont et al., 2015; Decker et al., 2017; Momozawa et al, 2018; Matejcic et al., 2020; Lattimore et al., 2021); This variant is associated with the following publications: (PMID: 25575445, 22941656, 32832836, 30287823, 28779002, 33113089, 31214711) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 15, 2022 | The frequency of this variant in the general population, 0.000087 (3/34592 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer and unaffected controls in the published literature (PMIDs: 30287823 (2018), 28779002 (2017), 25575445 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 04, 2023 | This missense variant replaces threonine with methionine at codon 696 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual and a family affected with breast cancer (PMID: 25575445, 33113089) and in breast cancer case-control studies in 1/13824 cases and 0/5488 unaffected individuals (PMID: 28779002) and in 2/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010449). This variant also has been reported in male breast cancer, pancreatic cancer and prostate cancer case-control studies, in which the variant is only detected in unaffected individuals and not found in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 4/251484 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2023 | The p.T696M variant (also known as c.2087C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2087. The threonine at codon 696 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in individuals with a personal or family history of breast cancer (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590) This variant was present in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43) but was only seen in one individual from the control group in a Japanese study of prostate cancer patients (Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial cancer of breast Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 06, 2024 | - - |
PALB2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 18, 2023 | The PALB2 c.2087C>T variant is predicted to result in the amino acid substitution p.Thr696Met. This variant was reported in individuals with breast cancer (Nguyen-Dumont et al. 2015. PubMed ID: 25575445; Supplemental Data 2, Momozawa et al. 2018. PubMed ID: 30287823; Table S5, Decker et al. 2017. PubMed ID: 28779002). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641388-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/136131/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 14, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at