chr16-23621414-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_024675.4(PALB2):c.3061G>A(p.Gly1021Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G1021E) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3061G>A | p.Gly1021Arg | missense_variant | 10/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3061G>A | p.Gly1021Arg | missense_variant | 10/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.420-2486C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251450Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135904
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461812Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727206
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 30, 2023 | This variant is considered likely 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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1021 of the PALB2 protein (p.Gly1021Arg). This variant is present in population databases (rs143808171, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 25575445, 35610400). ClinVar contains an entry for this variant (Variation ID: 230665). 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 expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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 | Counsyl | May 10, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2023 | The p.G1021R variant (also known as c.3061G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3061. The glycine at codon 1021 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in 1/1240 probands from the Breast Cancer Family Registry who had previously screened negative for BRCA1 and BRCA2 mutations (Nguyen-Dumont T et al. Breast Cancer Res. Treat., 2015 Jan;149:547-54). This alteration was also found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 Mar;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 | Jul 26, 2022 | This missense variant replaces glycine with arginine at codon 1021 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). A functional study has shown the mutant protein to exhibit 80% of wild-type activity in a homology-directed repair assay (PMID: 31636395). This variant has been reported in an individual affected with pancreatic cancer (PMID: 33127389). This variant has been identified in 2/251450 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 19, 2022 | Variant summary: PALB2 c.3061G>A (p.Gly1021Arg) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3061G>A has been reported in the literature in an individual (who was negative for BRCA1 and BRCA2 mutations) with a personal and/or family history of breast cancer (Nguyen-Dumont_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been found in an internal LCA sample (CHEK2 c.1100delC, (p.Thr367MetfsX15)), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated this missense change did not significantly affect PALB2 function in in a homology-directed DNA repair (HDR) assay (Wiltshire_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
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 | Jan 10, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest an intermediate effect on homology-directed repair (HDR) activity (Wiltshire et al., 2020); Observed in individuals with a personal and family history suggestive of hereditary breast and ovarian cancer (Nguyen-Dumont et al., 2015; Gonzalez et al., 2022); This variant is associated with the following publications: (PMID: 25575445, 31636395, 33195396, 35610400) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at