2-47478333-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong
The NM_000251.3(MSH2):c.2272G>A(p.Asp758Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. D758Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2272G>A | p.Asp758Asn | missense_variant | 14/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2272G>A | p.Asp758Asn | missense_variant | 14/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461788Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727190
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2024 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 758 of the MSH2 protein (p.Asp758Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with endometrial cancer (PMID: 30238922). ClinVar contains an entry for this variant (Variation ID: 408498). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2020 | The p.D758N variant (also known as c.2272G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2272. The aspartic acid at codon 758 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a patient with endometrial cancer diagnosed at age 41 with a family history of colorectal cancer in their father at age 80 (Özdemir TR et al. Balkan Med J, 2019 01;36:37-42). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at