chr16-23635449-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_024675.4(PALB2):āc.1097A>Gā(p.Asn366Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,774 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N366D) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.1097A>G | p.Asn366Ser | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1097A>G | p.Asn366Ser | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251372Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461774Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727210
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 366 of the PALB2 protein (p.Asn366Ser). This variant is present in population databases (rs554849907, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 185365). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 05, 2024 | 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]. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 2019 | - - |
PALB2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 13, 2023 | The PALB2 c.1097A>G variant is predicted to result in the amino acid substitution p.Asn366Ser. This variant was reported in individuals with breast and/or ovarian cancer (Table S2, Chan et al. 2018. PubMed ID: 30093976; Table S1, Hauke et al. 2018. PubMed ID: 29522266). It has also been reported in a control individual from an ovarian cancer cohort study (Table S4, Ramus et al. 2015. PubMed ID: 26315354). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/185365/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at