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]
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  • 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_000249.4(MLH1):c.1667G>A (p.Ser556Asn)

CA352060789

449776 (ClinVar)

Gene: MLH1
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 92a4b4e6-b758-4063-8f37-f656e1cb8728
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.1667G>A
NM_000249.4(MLH1):c.1667G>A (p.Ser556Asn)
NC_000003.12:g.37040294G>A
CM000665.2:g.37040294G>A
NC_000003.11:g.37081785G>A
CM000665.1:g.37081785G>A
NC_000003.10:g.37056789G>A
NG_007109.2:g.51945G>A
ENST00000413740.2:c.1667G>A
ENST00000429117.6:c.1373G>A
ENST00000450420.6:c.1559-10192G>A
ENST00000456676.7:c.1667G>A
ENST00000492474.6:c.944G>A
ENST00000616768.6:c.1667G>A
ENST00000673673.2:c.1667G>A
ENST00000231790.8:c.1667G>A
ENST00000413212.2:c.*585G>A
ENST00000432299.6:c.*1499G>A
ENST00000441265.6:c.944G>A
ENST00000447829.6:c.*778G>A
ENST00000539477.6:c.944G>A
ENST00000616768.5:c.704G>A
ENST00000673673.1:c.1620G>A
ENST00000673715.1:c.1667G>A
ENST00000673889.1:n.1049G>A
ENST00000673897.1:c.*1459G>A
ENST00000673899.1:c.935G>A
ENST00000673947.1:c.*1807G>A
ENST00000673972.1:c.*1545G>A
ENST00000673990.1:n.1558G>A
ENST00000674019.1:c.944G>A
ENST00000674111.1:c.1667G>A
ENST00000674125.1:n.378G>A
ENST00000231790.6:c.1667G>A
ENST00000413740.1:c.290G>A
ENST00000435176.5:c.1373G>A
ENST00000450420.5:c.182-10192G>A
ENST00000455445.6:c.944G>A
ENST00000456676.6:c.1642G>A
ENST00000458205.6:c.944G>A
ENST00000536378.5:c.944G>A
ENST00000539477.5:c.944G>A
ENST00000616768.4:c.435G>A
NM_000249.3:c.1667G>A
NM_001167617.1:c.1373G>A
NM_001167618.1:c.944G>A
NM_001167619.1:c.944G>A
NM_001258271.1:c.1667G>A
NM_001258273.1:c.944G>A
NM_001258274.1:c.944G>A
NM_001167617.2:c.1373G>A
NM_001167618.2:c.944G>A
NM_001167619.2:c.944G>A
NM_001258274.2:c.944G>A
NM_001354615.1:c.944G>A
NM_001354616.1:c.944G>A
NM_001354617.1:c.944G>A
NM_001354618.1:c.944G>A
NM_001354619.1:c.944G>A
NM_001354620.1:c.1373G>A
NM_001354621.1:c.644G>A
NM_001354622.1:c.644G>A
NM_001354623.1:c.644G>A
NM_001354624.1:c.593G>A
NM_001354625.1:c.593G>A
NM_001354626.1:c.593G>A
NM_001354627.1:c.593G>A
NM_001354628.1:c.1667G>A
NM_001354629.1:c.1568G>A
NM_001354630.1:c.1667G>A
NM_001167617.3:c.1373G>A
NM_001167618.3:c.944G>A
NM_001167619.3:c.944G>A
NM_001258271.2:c.1667G>A
NM_001258273.2:c.944G>A
NM_001258274.3:c.944G>A
NM_001354615.2:c.944G>A
NM_001354616.2:c.944G>A
NM_001354617.2:c.944G>A
NM_001354618.2:c.944G>A
NM_001354619.2:c.944G>A
NM_001354620.2:c.1373G>A
NM_001354621.2:c.644G>A
NM_001354622.2:c.644G>A
NM_001354623.2:c.644G>A
NM_001354624.2:c.593G>A
NM_001354625.2:c.593G>A
NM_001354626.2:c.593G>A
NM_001354627.2:c.593G>A
NM_001354628.2:c.1667G>A
NM_001354629.2:c.1568G>A
NM_001354630.2:c.1667G>A

Likely Pathogenic

Met criteria codes 3
PVS1_Strong PP4_Moderate PM2_Supporting
Not Met criteria codes 1
PS3

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 MLH1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The NM_000249.4: c.1667G>A variant in MLH1 is a missense variant predicted to cause substitution of Serin by Asparagin at amino acid 556 (p.Ser556Asn). PVS1_STR is met since c.1667G>A is a G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. The variant is not reported in gnomAD v4.1 (PM2_supporting). The variant was detected in 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1_STR, PM2_SUP, PP4 (VCEP specifications version 1)
Met criteria codes
PVS1_Strong
G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT
PP4_Moderate
>2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location.
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and gnomAD v4.1
Not Met criteria codes
PS3
Functional odds: 2.37 (CIMRA Functional Odds for Pathogenicity >2.08), so PS3_SUP. But since criteria PVS1 is used, PS3 should not be applied, (double counting)
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