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.1889T>A (p.Ile630Asn)

CA352065368

619511 (ClinVar)

Gene: MLH1
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c7dfdecb-28d6-4ff6-906c-a1c68da05a60
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.1889T>A
NM_000249.4(MLH1):c.1889T>A (p.Ile630Asn)
NC_000003.12:g.37047676T>A
CM000665.2:g.37047676T>A
NC_000003.11:g.37089167T>A
CM000665.1:g.37089167T>A
NC_000003.10:g.37064171T>A
NG_007109.2:g.59327T>A
ENST00000413740.2:c.1668-2810T>A
ENST00000429117.6:c.1595T>A
ENST00000450420.6:c.1559-2810T>A
ENST00000456676.7:c.1889T>A
ENST00000492474.6:c.1166T>A
ENST00000616768.6:c.1889T>A
ENST00000673673.2:c.1732-841T>A
ENST00000231790.8:c.1889T>A
ENST00000413212.2:c.*807T>A
ENST00000432299.6:c.*1721T>A
ENST00000441265.6:c.*118T>A
ENST00000447829.6:c.*1000T>A
ENST00000539477.6:c.1166T>A
ENST00000616768.5:c.926T>A
ENST00000673673.1:c.1685-841T>A
ENST00000673715.1:c.1889T>A
ENST00000673741.1:n.923T>A
ENST00000673889.1:n.1271T>A
ENST00000673897.1:c.*1681T>A
ENST00000673899.1:c.1157T>A
ENST00000673947.1:c.*2029T>A
ENST00000673972.1:c.*1767T>A
ENST00000674019.1:c.1166T>A
ENST00000674111.1:c.*118T>A
ENST00000674125.1:n.600T>A
ENST00000231790.6:c.1889T>A
ENST00000413740.1:c.291-2810T>A
ENST00000435176.5:c.1595T>A
ENST00000450420.5:c.182-2810T>A
ENST00000455445.6:c.1166T>A
ENST00000456676.6:c.1864T>A
ENST00000458205.6:c.1166T>A
ENST00000536378.5:c.1166T>A
ENST00000539477.5:c.1166T>A
ENST00000616768.4:c.657T>A
NM_000249.3:c.1889T>A
NM_001167617.1:c.1595T>A
NM_001167618.1:c.1166T>A
NM_001167619.1:c.1166T>A
NM_001258271.1:c.1889T>A
NM_001258273.1:c.1166T>A
NM_001258274.1:c.1166T>A
NM_001167617.2:c.1595T>A
NM_001167618.2:c.1166T>A
NM_001167619.2:c.1166T>A
NM_001258274.2:c.1166T>A
NM_001354615.1:c.1166T>A
NM_001354616.1:c.1166T>A
NM_001354617.1:c.1166T>A
NM_001354618.1:c.1166T>A
NM_001354619.1:c.1166T>A
NM_001354620.1:c.1595T>A
NM_001354621.1:c.866T>A
NM_001354622.1:c.866T>A
NM_001354623.1:c.866T>A
NM_001354624.1:c.815T>A
NM_001354625.1:c.815T>A
NM_001354626.1:c.815T>A
NM_001354627.1:c.815T>A
NM_001354628.1:c.1889T>A
NM_001354629.1:c.1790T>A
NM_001354630.1:c.1732-841T>A
NM_001167617.3:c.1595T>A
NM_001167618.3:c.1166T>A
NM_001167619.3:c.1166T>A
NM_001258271.2:c.1889T>A
NM_001258273.2:c.1166T>A
NM_001258274.3:c.1166T>A
NM_001354615.2:c.1166T>A
NM_001354616.2:c.1166T>A
NM_001354617.2:c.1166T>A
NM_001354618.2:c.1166T>A
NM_001354619.2:c.1166T>A
NM_001354620.2:c.1595T>A
NM_001354621.2:c.866T>A
NM_001354622.2:c.866T>A
NM_001354623.2:c.866T>A
NM_001354624.2:c.815T>A
NM_001354625.2:c.815T>A
NM_001354626.2:c.815T>A
NM_001354627.2:c.815T>A
NM_001354628.2:c.1889T>A
NM_001354629.2:c.1790T>A
NM_001354630.2:c.1732-841T>A

Uncertain Significance

Met criteria codes 4
PM2_Supporting PP3_Moderate PP4 PP1

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(MLH1):c.1889T>A (p.Ile630Asn) variant is a missense variant predicted to cause substitution of Isoleucin by Asparagin at amino acid 630 (p.Ile630Asn). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_Supporting). The variant meets the MMR-VCEP specific modifications for PP1, since the co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio is 2,23 (>2.08 & ≤4.32). The variant meets the MMR-VCEP specific modifications for PP4, since it has been detected in One CRC MSI-H tumour using a standard panel of 5-10 markersg and/or loss of MMR protein expression consistent with the variant location. The missense variant has a prior probability for pathogenicity >0.81 (PP3_Mod met). In summary there is insufficient evidence (VUS) (VCEP specifications version 1)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_Supporting).
PP3_Moderate
Missense variant with a prior probability for pathogenicity >0.81. Prior = 0,82. (PP3_Mod met). hci-priors.hci.utah.edu/PRIORS/
PP4
MSI-H/MLH1&PMS2 loss
PP1
Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratioh >2.08 & ≤4.32. Met, since segregation odds path = 2,23, (PP1)
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