rs180177125
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_024675.4(PALB2):āc.2773G>Cā(p.Val925Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,607,262 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 Uncertain significance (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V925M) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2773G>C | p.Val925Leu | missense_variant | 8/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2773G>C | p.Val925Leu | missense_variant | 8/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.590C>G | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250490Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135624
GnomAD4 exome AF: 0.0000309 AC: 45AN: 1455124Hom.: 0 Cov.: 30 AF XY: 0.0000373 AC XY: 27AN XY: 724318
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74306
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 27, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the PALB2 protein (p.Val925Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 18288683, 19763884, 29052111). ClinVar contains an entry for this variant (Variation ID: 126681). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 11, 2022 | - - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | Sep 30, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 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 breast, ovarian, prostate, or colon cancer (Tischkowitz et al., 2008; Papi et al., 2010; Maxwell et al., 2016; DeRycke et al., 2017; Myszka et al., 2017); This variant is associated with the following publications: (PMID: 18288683, 19763884, 26635394, 29052111, 27153395, 24485656, 19609323, 20871615, 17420451, 28944238) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2023 | The p.V925L variant (also known as c.2773G>C), located in coding exon 8 of the PALB2 gene, results from a G to C substitution at nucleotide position 2773. The valine at codon 925 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one individual from a cohort of 95 prostate cancer families and thought unlikely to be pathogenic by authors (Tischkowitz M et al. Prostate. 2008 May;68(6):675-8). This variant was also identified in a patient with colorectal cancer who met Amsterdam criteria whose tumor was mismatch repair proficient (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Another study detected this alteration in 1/338 breast cancer patients and 0/89 ovarian cancer patients from Poland and Ukraine (Myszka A et al. Fam. Cancer. 2018 07;17:345-349). This amino acid position is not well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 05, 2023 | This missense variant replaces valine with leucine at codon 925 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 individuals affected with breast and prostate cancer in the literature (PMID: 18288683, 19763884, 29052111, 29522266) and in a breast cancer case-control meta-analysis in 6/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010124). This variant has been identified in 4/245296 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. - |
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 | Mar 23, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at