chr16-23636175-G-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_024675.4(PALB2):c.371C>A(p.Thr124Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,670 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T124I) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.371C>A | p.Thr124Asn | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.371C>A | p.Thr124Asn | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460670Hom.: 1 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726582
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2023 | The p.T124N variant (also known as c.371C>A), located in coding exon 4 of the PALB2 gene, results from a C to A substitution at nucleotide position 371. The threonine at codon 124 is replaced by asparagine, an amino acid with similar properties. This alteration was observed in unselected female breast cancer patients, unselected prostate cancer patients and unaffected controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is poorly 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This missense variant replaces threonine with asparagine at codon 124 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two breast cancer case-control studies in which it was detected in 2 cases and 2 unaffected individuals (PMID: 30287823, 33471991). This variant also has been reported in a pancreatic cancer and a prostate cancer case-control study in 1/1005 pancreatic cancer cases and 4/23705 unaffected controls and 3/7636 prostate cancer cases and 2/12366 unaffected controls, respectively (PMID: 31214711, 32980694). This variant has not been identified 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individuals with breast cancer as well as unaffected control individuals (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 124 of the PALB2 protein (p.Thr124Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 449580). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at