Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000251.3(MSH2):c.1276G>A (p.Gly426Arg)

CA10584213

246389 (ClinVar)

Gene: MSH2
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e66339ca-8203-4b20-b52b-88e0f1339735
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000251.3:c.1276G>A
NM_000251.3(MSH2):c.1276G>A (p.Gly426Arg)
NC_000002.12:g.47429941G>A
CM000664.2:g.47429941G>A
NC_000002.11:g.47657080G>A
CM000664.1:g.47657080G>A
NC_000002.10:g.47510584G>A
NG_007110.2:g.31818G>A
ENST00000644900.2:c.1276G>A
ENST00000233146.7:c.1276G>A
ENST00000543555.6:c.1078G>A
ENST00000644092.1:c.1276G>A
ENST00000645339.1:c.1276G>A
ENST00000645506.1:c.1276G>A
ENST00000646415.1:c.1276G>A
ENST00000233146.6:c.1276G>A
ENST00000406134.5:c.1276G>A
ENST00000543555.5:c.1078G>A
ENST00000610696.4:c.1276G>A
ENST00000613514.4:c.1276G>A
ENST00000617333.3:c.*42G>A
ENST00000617938.4:c.*248G>A
ENST00000621359.2:c.1276G>A
NM_000251.2:c.1276G>A
NM_001258281.1:c.1078G>A
More

Pathogenic

Met criteria codes 3
PM2_Supporting PP4 PVS1
Not Met criteria codes 23
BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP2 BP4 BP1 PS1 PS3 PS2 PS4 BA1 PP1 PP3 PP2 PM5 PM1 PM4 PM3 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
NM_000251.3(MSH2):c.1276G>A variant results in a splicing aberration according to mRNA assay using RNA derived from patient constitutional biological samples which indicate that the variant allele (with evidence that the variant allele produces no full-length/reference transcript) leads to an in-frame deletion disrupting the lever domain and MSH6/MSH3 interaction domain (PMID: 28577310). Confirmed by minigene assay (LOVD Variant #0000846861). In addition, there is 1 endometrial tumour with loss of MSH2/MSH6 expression (PMID: 28577310). The variant is absent from gnomAD v4.1. Therefore, this variant is classified as pathogenic. (VCEP specifications version 1)
Met criteria codes
PM2_Supporting
Absent in gnomAD v2.1, v3.1 and v4.1
PP4
1 endometrial tumour with loss of MSH2/MSH6 expression (PMID: 28577310)
PVS1
Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to an in-frame deletion disrupting the lever domain and MSH6/MSH3 interaction domain (PMID: 28577310). Confirmed by minigene assay (LOVD Variant #0000846861).
Not Met criteria codes
BS3
The benign functional assay result is not relevant, because the variant alters splicing
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
See PVS1
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
NA
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Segregation odds of pathogenicity <2.08
PP3
NA - G in last base of exon
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Not required to reach pathogenic
PM1
NA
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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