NM_000249.4(MLH1):c.1766C>A (p.Ala589Asp) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 21, 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:: RCV003451065.1

Allele description [Variation Report for NM_000249.4(MLH1):c.1766C>A (p.Ala589Asp)]

NM_000249.4(MLH1):c.1766C>A (p.Ala589Asp)

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.1766C>A (p.Ala589Asp)

HGVS:

NC_000003.12:g.37047553C>A
NG_007109.2:g.59204C>A
NM_000249.4:c.1766C>AMANE SELECT
NM_001167617.3:c.1472C>A
NM_001167618.3:c.1043C>A
NM_001167619.3:c.1043C>A
NM_001258271.2:c.1766C>A
NM_001258273.2:c.1043C>A
NM_001258274.3:c.1043C>A
NM_001354615.2:c.1043C>A
NM_001354616.2:c.1043C>A
NM_001354617.2:c.1043C>A
NM_001354618.2:c.1043C>A
NM_001354619.2:c.1043C>A
NM_001354620.2:c.1472C>A
NM_001354621.2:c.743C>A
NM_001354622.2:c.743C>A
NM_001354623.2:c.743C>A
NM_001354624.2:c.692C>A
NM_001354625.2:c.692C>A
NM_001354626.2:c.692C>A
NM_001354627.2:c.692C>A
NM_001354628.2:c.1766C>A
NM_001354629.2:c.1667C>A
NM_001354630.2:c.1732-964C>A
NP_000240.1:p.Ala589Asp
NP_000240.1:p.Ala589Asp
NP_001161089.1:p.Ala491Asp
NP_001161090.1:p.Ala348Asp
NP_001161091.1:p.Ala348Asp
NP_001245200.1:p.Ala589Asp
NP_001245202.1:p.Ala348Asp
NP_001245203.1:p.Ala348Asp
NP_001341544.1:p.Ala348Asp
NP_001341545.1:p.Ala348Asp
NP_001341546.1:p.Ala348Asp
NP_001341547.1:p.Ala348Asp
NP_001341548.1:p.Ala348Asp
NP_001341549.1:p.Ala491Asp
NP_001341550.1:p.Ala248Asp
NP_001341551.1:p.Ala248Asp
NP_001341552.1:p.Ala248Asp
NP_001341553.1:p.Ala231Asp
NP_001341554.1:p.Ala231Asp
NP_001341555.1:p.Ala231Asp
NP_001341556.1:p.Ala231Asp
NP_001341557.1:p.Ala589Asp
NP_001341558.1:p.Ala556Asp
LRG_216t1:c.1766C>A
LRG_216:g.59204C>A
LRG_216p1:p.Ala589Asp
NC_000003.11:g.37089044C>A
NM_000249.3:c.1766C>A
P40692:p.Ala589Asp

Protein change:

A231D

Links:

UniProtKB: P40692#VAR_043419; dbSNP: rs63750016

NCBI 1000 Genomes Browser:

rs63750016

Molecular consequence:

NM_001354630.2:c.1732-964C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1766C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1472C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1766C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1043C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1472C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.743C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.743C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.743C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.692C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.692C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.692C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.692C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1766C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1667C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004185872	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jul 21, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20020535, 31784484, 16083711, 21404117 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004185872

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Jul 21, 2023)

unknown

clinical testing

PubMed (4)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1.

Drost M, Zonneveld Je, van Dijk L, Morreau H, Tops CM, Vasen HF, Wijnen JT, de Wind N.

Hum Mutat. 2010 Mar;31(3):247-53. doi: 10.1002/humu.21180.

PubMed [citation]

PMID:: 20020535

Three-step site-directed mutagenesis screen identifies pathogenic MLH1 variants associated with Lynch syndrome.

Houlleberghs H, Dekker M, Lusseveld J, Pieters W, van Ravesteyn T, Verhoef S, Hofstra RMW, Te Riele H.

J Med Genet. 2020 May;57(5):308-315. doi: 10.1136/jmedgenet-2019-106520. Epub 2019 Nov 29.

PubMed [citation]

PMID:: 31784484

See all PubMed Citations (4)

Details of each submission

From Myriad Genetics, Inc., SCV004185872.1

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

Description

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20020535, 31784484]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16083711, 21404117]. This variant is expected to disrupt protein structure [Myriad internal data].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 30, 2023

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