NM_000249.4(MLH1):c.637G>T (p.Val213Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 15, 2024
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:: RCV000774696.8

Allele description [Variation Report for NM_000249.4(MLH1):c.637G>T (p.Val213Leu)]

NM_000249.4(MLH1):c.637G>T (p.Val213Leu)

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.637G>T (p.Val213Leu)

HGVS:

NC_000003.12:g.37012059G>T
NG_007109.2:g.23710G>T
NM_000249.4:c.637G>TMANE SELECT
NM_001167617.3:c.343G>T
NM_001167618.3:c.-87G>T
NM_001167619.3:c.-87G>T
NM_001258271.2:c.637G>T
NM_001258273.2:c.-87G>T
NM_001258274.3:c.-87G>T
NM_001354615.2:c.-87G>T
NM_001354616.2:c.-87G>T
NM_001354617.2:c.-87G>T
NM_001354618.2:c.-87G>T
NM_001354619.2:c.-87G>T
NM_001354620.2:c.343G>T
NM_001354621.2:c.-180G>T
NM_001354622.2:c.-293G>T
NM_001354623.2:c.-293G>T
NM_001354624.2:c.-190G>T
NM_001354625.2:c.-190G>T
NM_001354626.2:c.-190G>T
NM_001354627.2:c.-190G>T
NM_001354628.2:c.637G>T
NM_001354629.2:c.538G>T
NM_001354630.2:c.637G>T
NP_000240.1:p.Val213Leu
NP_000240.1:p.Val213Leu
NP_001161089.1:p.Val115Leu
NP_001245200.1:p.Val213Leu
NP_001341549.1:p.Val115Leu
NP_001341557.1:p.Val213Leu
NP_001341558.1:p.Val180Leu
NP_001341559.1:p.Val213Leu
LRG_216t1:c.637G>T
LRG_216:g.23710G>T
LRG_216p1:p.Val213Leu
NC_000003.11:g.37053550G>T
NM_000249.3:c.637G>T

Protein change:

V115L

Links:

dbSNP: rs2308317

NCBI 1000 Genomes Browser:

rs2308317

Molecular consequence:

NM_001167618.3:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-87G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-180G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-293G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-293G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-190G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-190G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-190G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-190G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.637G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.343G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.637G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.343G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.637G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.538G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.637G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000908610	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15613555, 16810763, 28494185, 25741868
SCV001187344	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 15, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000908610

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 16, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001187344

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 15, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Genetic characterization of Chinese hereditary non-polyposis colorectal cancer by DHPLC and multiplex PCR.

Yuan Y, Huang YQ, Cai SR, Song YM, Zheng S, Zhang SZ.

Jpn J Clin Oncol. 2004 Nov;34(11):660-6.

PubMed [citation]

PMID:: 15613555

Clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer families.

Wang XL, Yuan Y, Zhang SZ, Cai SR, Huang YQ, Jiang Q, Zheng S.

World J Gastroenterol. 2006 Jul 7;12(25):4074-7.

PubMed [citation]

PMID:: 16810763
PMCID:: PMC4087725

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000908610.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces valine with leucine at codon 213 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study demonstrated this variant has no impact on RNA or protein expression (PMID: 28494185). This variant has been reported in a family affected with Lynch syndrome (PMID: 16810763, 15613555). This variant has been identified in 2/251170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

From Ambry Genetics, SCV001187344.4

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

Description

The p.V213L variant (also known as c.637G>T), located in coding exon 8 of the MLH1 gene, results from a G to T substitution at nucleotide position 637. The valine at codon 213 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a Chinese HNPCC family; however, no additional clinical details of the family were outlined (Wang XL et al. World J. Gastroenterol. 2006 Jul;12(25):4074-7). Functional studies have shown that this alteration results in both protein expression and mRNA expression similar to that of wild-type MLH1 (Arora S et al. Cancer Biol. Ther. 2017 Jul;18(7):519-533). This alteration was also identified in 1 of 1009 patients amongst a cohort of Chinese patients with a personal history of pancreatic ductal adenocarcinoma (Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

#	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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