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NM_000249.4(MLH1):c.1517T>C (p.Val506Ala) AND MLH1-related disorder

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 1, 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:
RCV003398662.4

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:
MLH1-related disorder
Synonyms:
MLH1-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004111858PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Mar 1, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004111858.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The MLH1 c.1517T>C variant is predicted to result in the amino acid substitution p.Val506Ala. This variant has been reported in families with hereditary non-polyposis colorectal cancer (Table 2, Liu et al. 1996. PubMed ID: 8574961; Table 3, Syngal et al. 1999. PubMed ID: 10422993; Table S1, Chao et al. 2008. PubMed ID: 18383312). It has been reported in individuals undergoing Lynch syndrome population screening, as well as an unaffected individual from a breast cancer cohort study (Table S3, Grzymski et al. 2020. PubMed ID: 32719484; Table S3, Palmer et al. 2020. PubMed ID: 32427313). In vitro experimental studies suggest this variant leads to reduced binding to hPMS2, reduced MMR activity, and reduced protein expression (Guerrette et al. 1999. PubMed ID: 10037723; Figure 1, Hinrichsen et al. 2013. PubMed ID: 23403630; Table S1, Ou et al. 2007. PubMed ID: 17594722; Table 1, Takahashi et al. 2007. PubMed ID: 17510385). In vivo experimental studies suggest this variant reduces binding to EXO1 and inactivates the dominant negative phenotype of hMLH1 in some strains of yeast (Table 1, Figure 3b, Shimodaira et al. 1998. PubMed ID: 9697702; Table 1, Kondo et al 2003. PubMed ID: 12810663; Table 1, Takahashi et al. 2007. PubMed ID: 17510385). This variant is reported in 1 of ~31,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/3-37070382-T-C). It is interpreted as likely pathogenic by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/89757/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024