chr16-23635504-G-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_024675.4(PALB2):c.1042C>A(p.Gln348Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q348Q) 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.1042C>A | p.Gln348Lys | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1042C>A | p.Gln348Lys | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251120Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135772
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461558Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727094
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74338
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:3Benign:1
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 05, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 348 of the PALB2 protein (p.Gln348Lys). This variant is present in population databases (rs375699023, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141588). 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 16, 2020 | Variant summary: PALB2 c.1042C>A (p.Gln348Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 257982 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.00016), allowing no conclusion about variant significance. c.1042C>A has been reported in the literature in at least one individual affected with breast cancer (Decker_2017), but also in healthy controls (Ramus_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant associated with Hereditary Breast and Ovarian Cancer has been reported in an internal sample (BRCA2 c.9789_9790delGA , p.Asn3264LeufsX12), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as likely benign (n=1) and uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 07, 2021 | DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.1042C>A, in exon 4 that results in an amino acid change, p.Gln348Lys. This sequence change has been described in gnomAD with a frequency of 0.0085% in the Non-Finnish European sub-population (dbSNP rs375699023). The p.Gln348Lys change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. The p.Gln348Lys substitution appears to be tolerated using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with PALB2-related. Due to the lack of sufficient evidences, the clinical significance of the p.Gln348Lys change remains unknown at this time. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The p.Q348K variant (also known as c.1042C>A), located in coding exon 4 of the PALB2 gene, results from a C to A substitution at nucleotide position 1042. The glutamine at codon 348 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 08, 2016 | - - |
Chordoma Uncertain:1
Uncertain significance, no assertion criteria provided | research | Integrative Tumor Epidemiology Branch, National Institutes of Health | Mar 22, 2021 | Modestly reduce HRR activity - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2024 | Published functional studies suggest no damaging effect: homologous recombination repair similar to wildtype and normal co-localization in the nucleus with BRCA1 (PMID: 35762214); In silico analysis supports that this missense variant does not alter protein structure/function; Observed to segregate in a single family with multiple individuals with chordoma or juvenile pilocytic astrocytoma, but was also present in unaffected individuals (PMID: 35762214); Identified in an individual with breast cancer (PMID: 28779002); This variant is associated with the following publications: (PMID: 26315354, 36387127, 35762214, 28779002) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at