NM_000249.4(MLH1):c.1517T>C (p.Val506Ala) AND Hereditary nonpolyposis colon cancer

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 27, 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:: RCV001778701.10

Allele description [Variation Report for NM_000249.4(MLH1):c.1517T>C (p.Val506Ala)]

NM_000249.4(MLH1):c.1517T>C (p.Val506Ala)

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.1517T>C (p.Val506Ala)

Other names:

p.V506A:GTT>GCT

HGVS:

NC_000003.12:g.37028891T>C
NG_007109.2:g.40542T>C
NM_000249.4:c.1517T>CMANE SELECT
NM_001167617.3:c.1223T>C
NM_001167618.3:c.794T>C
NM_001167619.3:c.794T>C
NM_001258271.2:c.1517T>C
NM_001258273.2:c.794T>C
NM_001258274.3:c.794T>C
NM_001354615.2:c.794T>C
NM_001354616.2:c.794T>C
NM_001354617.2:c.794T>C
NM_001354618.2:c.794T>C
NM_001354619.2:c.794T>C
NM_001354620.2:c.1223T>C
NM_001354621.2:c.494T>C
NM_001354622.2:c.494T>C
NM_001354623.2:c.494T>C
NM_001354624.2:c.443T>C
NM_001354625.2:c.443T>C
NM_001354626.2:c.443T>C
NM_001354627.2:c.443T>C
NM_001354628.2:c.1517T>C
NM_001354629.2:c.1418T>C
NM_001354630.2:c.1517T>C
NP_000240.1:p.Val506Ala
NP_000240.1:p.Val506Ala
NP_001161089.1:p.Val408Ala
NP_001161090.1:p.Val265Ala
NP_001161091.1:p.Val265Ala
NP_001245200.1:p.Val506Ala
NP_001245202.1:p.Val265Ala
NP_001245203.1:p.Val265Ala
NP_001341544.1:p.Val265Ala
NP_001341545.1:p.Val265Ala
NP_001341546.1:p.Val265Ala
NP_001341547.1:p.Val265Ala
NP_001341548.1:p.Val265Ala
NP_001341549.1:p.Val408Ala
NP_001341550.1:p.Val165Ala
NP_001341551.1:p.Val165Ala
NP_001341552.1:p.Val165Ala
NP_001341553.1:p.Val148Ala
NP_001341554.1:p.Val148Ala
NP_001341555.1:p.Val148Ala
NP_001341556.1:p.Val148Ala
NP_001341557.1:p.Val506Ala
NP_001341558.1:p.Val473Ala
NP_001341559.1:p.Val506Ala
LRG_216t1:c.1517T>C
LRG_216:g.40542T>C
LRG_216p1:p.Val506Ala
NC_000003.11:g.37070382T>C
NM_000249.3:c.1517T>C
NM_001167617.1:c.1223T>C
P40692:p.Val506Ala
p.V506A

Protein change:

V148A

Links:

UniProtKB: P40692#VAR_004456; dbSNP: rs63749909

NCBI 1000 Genomes Browser:

rs63749909

Molecular consequence:

NM_000249.4:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.794T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.494T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.494T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.494T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1418T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1517T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:: Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:: MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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PREDICTED: Homo sapiens ring finger protein 135 (RNF135), transcript variant X2,...
PREDICTED: Homo sapiens ring finger protein 135 (RNF135), transcript variant X2, mRNA
gi|2462499028|ref|XM_054333220.1|

Nucleotide
mixed-lineage leukemia-like protein, partial [Trachyrincus murrayi]
mixed-lineage leukemia-like protein, partial [Trachyrincus murrayi]
gi|33668759|gb|AAQ24749.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919651	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 27, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 12810663, 17510385, 18383312, 10422993, 8574961, 10037723, 9697702, 22426235, 23403630, 25980754, 28514183, 31784484, 32719484, 34404389, 32427313, 36054288 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919651

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 27, 2023)

germline

clinical testing

PubMed (16)
[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

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

Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C.

Cancer Res. 2007 May 15;67(10):4595-604.

PubMed [citation]

PMID:: 17510385

See all PubMed Citations (16)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919651.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: MLH1 c.1517T>C (p.Val506Ala) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-06 in 261636 control chromosomes (gnomAD). c.1517T>C has been reported in multiple colorectal cancer patients from families fulfilling the Amsterdam and the revised Bethesda criteria (e.g. Liu_1996, Chao_2008, Yurgelun_2015, Syngal_1999, Medeiros_2012). These data indicate that the variant is likely to be associated with disease. In in vitro functional studies, the variant showed reduced MLH1 expression and altered binding to PMS2 and EXO1, but mismatch repair (MMR) activity close to wild type (Shimodaira_1998, Guerrette_1999, Takahashi_2007, Hinrichsen_2013). Eight (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=7) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely 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: Nov 3, 2024

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