16-23637868-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_024675.4(PALB2):āc.193C>Gā(p.Pro65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,588 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65L) 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
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460588Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726710
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:1
ClinVar contains an entry for this variant (Variation ID: 482012). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 65 of the PALB2 protein (p.Pro65Ala). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Hereditary cancer-predisposing syndrome Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at