NM_000249.4(MLH1):c.152T>C (p.Val51Ala) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 30, 2017
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:: RCV000629750.4

Allele description [Variation Report for NM_000249.4(MLH1):c.152T>C (p.Val51Ala)]

NM_000249.4(MLH1):c.152T>C (p.Val51Ala)

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.152T>C (p.Val51Ala)

HGVS:

NC_000003.12:g.36996654T>C
NG_007109.2:g.8305T>C
NG_008418.1:g.1651A>G
NM_000249.4:c.152T>CMANE SELECT
NM_001167617.3:c.-138T>C
NM_001167618.3:c.-572T>C
NM_001167619.3:c.-480T>C
NM_001258271.2:c.152T>C
NM_001258273.2:c.-517+2991T>C
NM_001258274.3:c.-717T>C
NM_001354615.2:c.-475T>C
NM_001354616.2:c.-480T>C
NM_001354617.2:c.-572T>C
NM_001354618.2:c.-572T>C
NM_001354619.2:c.-572T>C
NM_001354620.2:c.-138T>C
NM_001354621.2:c.-665T>C
NM_001354622.2:c.-778T>C
NM_001354623.2:c.-723+2764T>C
NM_001354624.2:c.-675T>C
NM_001354625.2:c.-578T>C
NM_001354626.2:c.-675T>C
NM_001354627.2:c.-675T>C
NM_001354628.2:c.152T>C
NM_001354629.2:c.152T>C
NM_001354630.2:c.152T>C
NP_000240.1:p.Val51Ala
NP_000240.1:p.Val51Ala
NP_001245200.1:p.Val51Ala
NP_001341557.1:p.Val51Ala
NP_001341558.1:p.Val51Ala
NP_001341559.1:p.Val51Ala
LRG_216t1:c.152T>C
LRG_216:g.8305T>C
LRG_216p1:p.Val51Ala
NC_000003.11:g.37038145T>C
NM_000249.3:c.152T>C

Protein change:

V51A

Links:

dbSNP: rs1553638767

NCBI 1000 Genomes Browser:

rs1553638767

Molecular consequence:

NM_001167617.3:c.-138T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-572T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-480T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-717T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-475T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-480T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-572T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-572T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-572T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-138T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-665T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-778T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-675T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-578T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-675T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-675T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2991T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2764T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.152T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.152T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.152T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.152T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.152T>C - 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
SCV000750706	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 30, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15475387, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000750706

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 30, 2017)

germline

clinical testing

PubMed (2)
[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

Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.

Ellison AR, Lofing J, Bitter GA.

Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. Print 2004.

PubMed [citation]

PMID:: 15475387
PMCID:: PMC524276

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000750706.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An experimental study has shown that this missense change partially impairs the DNA mismatch repair activity of the MLH1 protein (PMID: 15475387). This variant has not been reported in the literature in individuals with MLH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 51 of the MLH1 protein (p.Val51Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.

#	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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