NM_000249.4(MLH1):c.554T>G (p.Val185Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 11, 2023
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:: RCV001385098.4

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 nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001584840	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 11, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9697702, 11781295, 12810663, 17510385, 17594722, 21120944, 24362816, 8808596, 16083711, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001584840

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 11, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae.

Shimodaira H, Filosi N, Shibata H, Suzuki T, Radice P, Kanamaru R, Friend SH, Kolodner RD, Ishioka C.

Nat Genet. 1998 Aug;19(4):384-9. Erratum in: Nat Genet 1999 Feb;21(2):241.

PubMed [citation]

PMID:: 9697702

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

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001584840.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 185 of the MLH1 protein (p.Val185Gly). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11781295, 12810663, 16083711, 17510385, 17594722, 21120944). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 90272). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 8808596, 16083711). It has also been observed to segregate with disease in related individuals.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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