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

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 27, 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:: RCV000524242.15

Allele description

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 colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Homo sapiens DPH2 homolog (S. cerevisiae), mRNA (cDNA clone MGC:1559 IMAGE:30514...
Homo sapiens DPH2 homolog (S. cerevisiae), mRNA (cDNA clone MGC:1559 IMAGE:3051455), complete cds
gi|33987995|gb|BC001389.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543586	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8574961, 10422993, 18383312, 9697702, 10037723, 12810663, 17510385, 23403630, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543586

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 27, 2024)

germline

clinical testing

PubMed (9)
[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

Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients.

Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomäki P, de la Chapelle A, Hamilton SR, Vogelstein B, Kinzler KW.

Nat Med. 1996 Feb;2(2):169-74.

PubMed [citation]

PMID:: 8574961

Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.

Syngal S, Fox EA, Li C, Dovidio M, Eng C, Kolodner RD, Garber JE.

JAMA. 1999 Jul 21;282(3):247-53.

PubMed [citation]

PMID:: 10422993

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000543586.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 506 of the MLH1 protein (p.Val506Ala). This variant is present in population databases (rs63749909, gnomAD 0.007%). This missense change has been observed in individuals with Lynch syndrome (PMID: 8574961, 10422993, 18383312; Invitae). ClinVar contains an entry for this variant (Variation ID: 89757). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 10037723, 12810663, 17510385, 23403630). For these reasons, this variant has been classified as 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 16, 2024

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