NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp) 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:: RCV003451062.1

Allele description [Variation Report for NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp)]

NM_000249.4(MLH1):c.1757C>A (p.Ala586Asp)

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.1757C>A (p.Ala586Asp)

HGVS:

NC_000003.12:g.37047544C>A
NG_007109.2:g.59195C>A
NM_000249.4:c.1757C>AMANE SELECT
NM_001167617.3:c.1463C>A
NM_001167618.3:c.1034C>A
NM_001167619.3:c.1034C>A
NM_001258271.2:c.1757C>A
NM_001258273.2:c.1034C>A
NM_001258274.3:c.1034C>A
NM_001354615.2:c.1034C>A
NM_001354616.2:c.1034C>A
NM_001354617.2:c.1034C>A
NM_001354618.2:c.1034C>A
NM_001354619.2:c.1034C>A
NM_001354620.2:c.1463C>A
NM_001354621.2:c.734C>A
NM_001354622.2:c.734C>A
NM_001354623.2:c.734C>A
NM_001354624.2:c.683C>A
NM_001354625.2:c.683C>A
NM_001354626.2:c.683C>A
NM_001354627.2:c.683C>A
NM_001354628.2:c.1757C>A
NM_001354629.2:c.1658C>A
NM_001354630.2:c.1732-973C>A
NP_000240.1:p.Ala586Asp
NP_000240.1:p.Ala586Asp
NP_001161089.1:p.Ala488Asp
NP_001161090.1:p.Ala345Asp
NP_001161091.1:p.Ala345Asp
NP_001245200.1:p.Ala586Asp
NP_001245202.1:p.Ala345Asp
NP_001245203.1:p.Ala345Asp
NP_001341544.1:p.Ala345Asp
NP_001341545.1:p.Ala345Asp
NP_001341546.1:p.Ala345Asp
NP_001341547.1:p.Ala345Asp
NP_001341548.1:p.Ala345Asp
NP_001341549.1:p.Ala488Asp
NP_001341550.1:p.Ala245Asp
NP_001341551.1:p.Ala245Asp
NP_001341552.1:p.Ala245Asp
NP_001341553.1:p.Ala228Asp
NP_001341554.1:p.Ala228Asp
NP_001341555.1:p.Ala228Asp
NP_001341556.1:p.Ala228Asp
NP_001341557.1:p.Ala586Asp
NP_001341558.1:p.Ala553Asp
LRG_216t1:c.1757C>A
LRG_216:g.59195C>A
LRG_216p1:p.Ala586Asp
NC_000003.11:g.37089035C>A
NM_000249.3:c.1757C>A

Protein change:

A228D

Links:

dbSNP: rs63750587

NCBI 1000 Genomes Browser:

rs63750587

Molecular consequence:

NM_001354630.2:c.1732-973C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1463C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1034C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1463C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.734C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.734C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.734C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.683C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1757C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1658C>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
SCV004188288	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 (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004188288

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

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

Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm.

Morris B, Hughes E, Rosenthal E, Gutin A, Bowles KR.

BMC Genet. 2016 Jul 1;17(1):99. doi: 10.1186/s12863-016-0407-0.

PubMed [citation]

PMID:: 27363726
PMCID:: PMC4929734

Details of each submission

From Myriad Genetics, Inc., SCV004188288.1

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

Description

This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].

#	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: May 1, 2024

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