rs730881783
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000251.3(MSH2):c.367-19A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,609,524 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00015 ( 1 hom. )
Consequence
MSH2
NM_000251.3 intron
NM_000251.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.250
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 Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 2-47410075-A-T is Benign according to our data. Variant chr2-47410075-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 182607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.367-19A>T | intron_variant | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.367-19A>T | intron_variant | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152178Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000526 AC: 13AN: 247176Hom.: 0 AF XY: 0.0000447 AC XY: 6AN XY: 134266
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GnomAD4 exome AF: 0.000154 AC: 224AN: 1457346Hom.: 1 Cov.: 31 AF XY: 0.000128 AC XY: 93AN XY: 725194
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152178Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74350
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2020 | Variant summary: MSH2 c.367-19A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.3e-05 in 247176 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.3e-05 vs 0.00057), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.367-19A>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign. - |
Lynch syndrome 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Oct 25, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 20, 2023 | This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. 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 nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 17, 2016 | - - |
Computational scores
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BayesDel_noAF
Benign
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DANN
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at