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NM_000249.4(MLH1):c.554T>G (p.Val185Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 2, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002345382.4

Allele description [Variation Report for NM_000249.4(MLH1):c.554T>G (p.Val185Gly)]

NM_000249.4(MLH1):c.554T>G (p.Val185Gly)

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.554T>G (p.Val185Gly)
HGVS:
  • NC_000003.12:g.37011828T>G
  • NG_007109.2:g.23479T>G
  • NM_000249.4:c.554T>GMANE SELECT
  • NM_001167617.3:c.260T>G
  • NM_001167618.3:c.-170T>G
  • NM_001167619.3:c.-170T>G
  • NM_001258271.2:c.554T>G
  • NM_001258273.2:c.-170T>G
  • NM_001258274.3:c.-170T>G
  • NM_001354615.2:c.-170T>G
  • NM_001354616.2:c.-170T>G
  • NM_001354617.2:c.-170T>G
  • NM_001354618.2:c.-170T>G
  • NM_001354619.2:c.-170T>G
  • NM_001354620.2:c.260T>G
  • NM_001354621.2:c.-263T>G
  • NM_001354622.2:c.-376T>G
  • NM_001354623.2:c.-376T>G
  • NM_001354624.2:c.-273T>G
  • NM_001354625.2:c.-273T>G
  • NM_001354626.2:c.-273T>G
  • NM_001354627.2:c.-273T>G
  • NM_001354628.2:c.554T>G
  • NM_001354629.2:c.455T>G
  • NM_001354630.2:c.554T>G
  • NP_000240.1:p.Val185Gly
  • NP_000240.1:p.Val185Gly
  • NP_001161089.1:p.Val87Gly
  • NP_001245200.1:p.Val185Gly
  • NP_001341549.1:p.Val87Gly
  • NP_001341557.1:p.Val185Gly
  • NP_001341558.1:p.Val152Gly
  • NP_001341559.1:p.Val185Gly
  • LRG_216t1:c.554T>G
  • LRG_216:g.23479T>G
  • LRG_216p1:p.Val185Gly
  • NC_000003.11:g.37053319T>G
  • NM_000249.3:c.554T>G
  • NM_001167618.1:c.-170T>G
  • P40692:p.Val185Gly
Protein change:
V152G
Links:
UniProtKB: P40692#VAR_004447; dbSNP: rs63750515
NCBI 1000 Genomes Browser:
rs63750515
Molecular consequence:
  • NM_001167618.3:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-263T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-376T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-376T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.260T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.260T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.455T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.554T>G - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002654031Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Apr 2, 2024)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.

Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G.

Gastroenterology. 2002 Jan;122(1):211-9.

PubMed [citation]
PMID:
11781295

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]
PMID:
12810663
See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002654031.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

The p.V185G variant (also known as c.554T>G), located in coding exon 7 of the MLH1 gene, results from a T to G substitution at nucleotide position 554. The valine at codon 185 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in a proband with colorectal cancer diagnosed at age 43 whose family met Amsterdam I criteria; the colorectal tumor was MSI-H and had reduced MLH1 expression on IHC (Raevaara TE et al. Gastroenterology. 2005 Aug;129:537-49). This alteration also showed deficient mismatch repair activity in complementation assays (Trojan J et al. Gastroenterology. 2002 Jan;122:211-9; Kondo E et al. Cancer Res. 2003 Jun;63:3302-8; Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024