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_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
More

Likely Pathogenic

Met criteria codes 3
PP4_Moderate PVS1_Strong 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
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.
PVS1_Strong
G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT
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)
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.