rs761032954
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_024675.4(PALB2):c.3035C>T(p.Thr1012Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251456Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135904
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461792Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 727204
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74338
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:5
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1012 of the PALB2 protein (p.Thr1012Ile). This variant is present in population databases (rs761032954, gnomAD 0.07%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 25980754, 26489409, 28825143, 33811135). ClinVar contains an entry for this variant (Variation ID: 410122). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 35853885). 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. -
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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. -
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not provided Uncertain:2
The PALB2 c.3035C>T (p.Thr1012Ile) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 26489409 (2015), 28825143 (2017), 33811135 (2022)) and an undescribed Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015)). This variant has also been reported in affected and reportedly healthy individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). One functional study observed the variant to have only a modest reduction in homologous recombination DNA repair (PMID: 35853885 (2022)), however further research is needed. The frequency of this variant in the general population, 0.00076 (11/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and other cancers (Li 2015, Yurgelun 2015, Zhang 2017); This variant is associated with the following publications: (PMID: 26489409, 25980754, 28825143, 26692951) -
Hereditary cancer-predisposing syndrome Benign:2
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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. -
Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at