NM_000249.4(MLH1):c.392C>A (p.Ser131Ter) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 13, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003388572.3

Allele description [Variation Report for NM_000249.4(MLH1):c.392C>A (p.Ser131Ter)]

NM_000249.4(MLH1):c.392C>A (p.Ser131Ter)

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.392C>A (p.Ser131Ter)

HGVS:

NC_000003.12:g.37007002C>A
NG_007109.2:g.18653C>A
NM_000249.4:c.392C>AMANE SELECT
NM_001167617.3:c.98C>A
NM_001167618.3:c.-332C>A
NM_001167619.3:c.-240C>A
NM_001258271.2:c.392C>A
NM_001258273.2:c.-332C>A
NM_001258274.3:c.-332C>A
NM_001354615.2:c.-240C>A
NM_001354616.2:c.-240C>A
NM_001354617.2:c.-332C>A
NM_001354618.2:c.-332C>A
NM_001354619.2:c.-332C>A
NM_001354620.2:c.98C>A
NM_001354621.2:c.-425C>A
NM_001354622.2:c.-538C>A
NM_001354623.2:c.-538C>A
NM_001354624.2:c.-435C>A
NM_001354625.2:c.-343C>A
NM_001354626.2:c.-435C>A
NM_001354627.2:c.-435C>A
NM_001354628.2:c.392C>A
NM_001354629.2:c.293C>A
NM_001354630.2:c.392C>A
NP_000240.1:p.Ser131Ter
NP_000240.1:p.Ser131Ter
NP_001161089.1:p.Ser33Ter
NP_001245200.1:p.Ser131Ter
NP_001341549.1:p.Ser33Ter
NP_001341557.1:p.Ser131Ter
NP_001341558.1:p.Ser98Ter
NP_001341559.1:p.Ser131Ter
LRG_216t1:c.392C>A
LRG_216:g.18653C>A
LRG_216p1:p.Ser131Ter
NC_000003.11:g.37048493C>A
NM_000249.3:c.392C>A

Protein change:

S131*

Links:

dbSNP: rs63749818

NCBI 1000 Genomes Browser:

rs63749818

Molecular consequence:

NM_001167618.3:c.-332C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-240C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-332C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-332C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-240C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-240C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-332C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-332C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-332C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-425C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-538C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-538C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-435C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-343C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-435C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-435C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.392C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.98C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.392C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.98C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.392C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.293C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.392C>A - nonsense - [Sequence Ontology: SO:0001587]

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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Homo sapiens potassium voltage-gated channel, subfamily G, member 3 (KCNG3), mRNA
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004100571	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004186468	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jul 13, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004100571

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

SCV004186468

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Jul 13, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 Neuberg Centre For Genomic Medicine, NCGM, SCV004100571.1

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

Description

The stop gained p.S131* in MLH1 (NM_000249.4) has been reported to ClinVar as Pathogenic, however details are not available for independent assessment. A different pathogenic variant having c.392C>G affecting the same p.Ser131Ter has been reported in at least four families meeting testing and/or clinical criteria for Lynch syndrome (Kurzawski 2006, Hiljadnikova-Bajro 2012) and is submitted as Pathogenic to ClinVar. The p.S131* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.S131* variant is a loss of function variant in the gene MLH1, which is intolerant of Loss of Function variants. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004186468.1

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

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	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 7, 2024

ClinVar

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