rs267607972
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000251.3(MSH2):c.1661+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MSH2
NM_000251.3 splice_region, intron
NM_000251.3 splice_region, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 5.12
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47466813-G-A is Pathogenic according to our data. Variant chr2-47466813-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 230181.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459884Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726360
GnomAD4 exome
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1459884
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32
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0
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726360
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary nonpolyposis colon cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2024 | Variant summary: MSH2 c.1661+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predicts the variant weakens a 5' donor site. One predicts the variant has no significant impact on splicing. Internal data suggests that this variant affects mRNA splicing by introducing frameshifts expected to result in nonsense mediated decay (Labcorp Genetics, formerly Invitae). The variant was absent in 250972 control chromosomes. c.1661+5G>A has been reported internally and in the literature in the presumed heterozygous state in multiple individuals affected with clinical features of Hereditary Nonpolyposis Colorectal Cancer (example, Roht_2022, Labcorp Genetics (formerly Invitae)). The following publications have been ascertained in the context of this evaluation (PMID: 36425062). ClinVar contains an entry for this variant (Variation ID: 230181). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lynch syndrome 1 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Genetics and Personalized Medicine Clinic, Tartu University Hospital | - | This variant fas found in a patient with colorectal cancer at the age of 60 year old. In family anamnesis gynecological cancers, no specific details known - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 12, 2022 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 230181). This variant has been observed in individual(s) with Lynch syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2024 | The c.1661+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the MSH2 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at