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NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 5, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000562335.11

Allele description [Variation Report for NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr)]

NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.230G>A (p.Cys77Tyr)
HGVS:
  • NC_000003.12:g.37000977G>A
  • NG_007109.2:g.12628G>A
  • NM_000249.4:c.230G>AMANE SELECT
  • NM_001167617.3:c.-60G>A
  • NM_001167618.3:c.-494G>A
  • NM_001167619.3:c.-402G>A
  • NM_001258271.2:c.230G>A
  • NM_001258273.2:c.-494G>A
  • NM_001258274.3:c.-494G>A
  • NM_001354615.2:c.-397G>A
  • NM_001354616.2:c.-402G>A
  • NM_001354617.2:c.-494G>A
  • NM_001354618.2:c.-494G>A
  • NM_001354619.2:c.-494G>A
  • NM_001354620.2:c.-60G>A
  • NM_001354621.2:c.-587G>A
  • NM_001354622.2:c.-700G>A
  • NM_001354623.2:c.-700G>A
  • NM_001354624.2:c.-597G>A
  • NM_001354625.2:c.-500G>A
  • NM_001354626.2:c.-597G>A
  • NM_001354627.2:c.-597G>A
  • NM_001354628.2:c.230G>A
  • NM_001354629.2:c.208-3424G>A
  • NM_001354630.2:c.230G>A
  • NP_000240.1:p.Cys77Tyr
  • NP_000240.1:p.Cys77Tyr
  • NP_001245200.1:p.Cys77Tyr
  • NP_001341557.1:p.Cys77Tyr
  • NP_001341559.1:p.Cys77Tyr
  • LRG_216t1:c.230G>A
  • LRG_216:g.12628G>A
  • LRG_216p1:p.Cys77Tyr
  • NC_000003.11:g.37042468G>A
  • NM_000249.3:c.230G>A
  • P40692:p.Cys77Tyr
Protein change:
C77Y
Links:
UniProtKB: P40692#VAR_012904; dbSNP: rs63750437
NCBI 1000 Genomes Browser:
rs63750437
Molecular consequence:
  • NM_001167617.3:c.-60G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-402G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-397G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-402G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-494G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-60G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-587G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-700G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-700G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-597G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-500G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-597G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-597G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354629.2:c.208-3424G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000676013Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Aug 5, 2023) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000689869Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Feb 1, 2023) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair.

Plotz G, Welsch C, Giron-Monzon L, Friedhoff P, Albrecht M, Piiper A, Biondi RM, Lengauer T, Zeuzem S, Raedle J.

Nucleic Acids Res. 2006;34(22):6574-86. Epub 2006 Nov 28.

PubMed [citation]
PMID:
17135187
PMCID:
PMC1747184

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]
PMID:
21520333
See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000676013.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The p.C77Y pathogenic mutation (also known as c.230G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 230. The cysteine at codon 77 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been identified in numerous individuals meeting Amsterdam criteria for Lynch syndrome with concordant tumor microsatellite and immunohistochemistry results (Hardt Ket al. Fam. Cancer. 2011 Jun; 10(2):273-84; Fokkema IF et al. Hum. Mutat. 2011 May; 32(5):557-63). Functional studies of the p.C77Y alteration have demonstrated impaired/reduced MLH1 expression, sub-cellular localization, and mismatch repair activity compared to wild-type MLH1 protein (Takahashi M et al. Cancer Res. 2007 May; 67(10):4595-604; Kondo E et al. Cancer Res. 2003 Jun; 63(12):3302-8; Wanat JJ et al. Hum. Mol. Genet. 2007 Feb;16(4):445-52; Shimodaira H et al. Nat. Genet. 1998 Aug; 19(4):384-9; Plotz G et al. Nucleic Acids Res. 2006;34(22):6574-86). Functional studies of another amino acid change at the same codon, p.C77R, have also shown impaired activity compared to wild-type (Nystrom-Lahti M et al. Genes Chromosomes Cancer. 2002 Feb;33(2):160-7; Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49). In addition, the p.C77Y alteration has been classified as definitely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000689869.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This missense variant replaces cysteine with tyrosine at codon 77 in the ATPase domain of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant reduces protein expression and stability, reduces the dominant negative mutator effect, and reduces DNA mismatch repair activity (PMID: 9697702, 12810663, 17210669, 17510385, 31697235). This variant has been reported in multiple individuals affected with Lynch Syndrome (PMID: 9032648, 15849733, 18383312, 21404117, 25420488, 26895986). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024