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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Homo sapiens proteasomal ATPase associated factor 1 (PAAF1), transcript variant 5, mRNA
gi|1890333849|ref|NM_001267806.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002654031	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 2, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11781295, 12810663, 16083711, 17192056, 17510385, 17594722, 21120944, 30998989, 8808596, 9697702 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002654031

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 2, 2024)

germline

clinical testing

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

Citation Link

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 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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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