NM_000249.4(MLH1):c.453G>A (p.Thr151=) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 17, 2024
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:: RCV000987151.8

Allele description [Variation Report for NM_000249.4(MLH1):c.453G>A (p.Thr151=)]

NM_000249.4(MLH1):c.453G>A (p.Thr151=)

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.453G>A (p.Thr151=)

HGVS:

NC_000003.12:g.37007063G>A
NG_007109.2:g.18714G>A
NM_000249.4:c.453G>AMANE SELECT
NM_001167617.3:c.159G>A
NM_001167618.3:c.-271G>A
NM_001167619.3:c.-179G>A
NM_001258271.2:c.453G>A
NM_001258273.2:c.-271G>A
NM_001258274.3:c.-271G>A
NM_001354615.2:c.-179G>A
NM_001354616.2:c.-179G>A
NM_001354617.2:c.-271G>A
NM_001354618.2:c.-271G>A
NM_001354619.2:c.-271G>A
NM_001354620.2:c.159G>A
NM_001354621.2:c.-364G>A
NM_001354622.2:c.-477G>A
NM_001354623.2:c.-477G>A
NM_001354624.2:c.-374G>A
NM_001354625.2:c.-282G>A
NM_001354626.2:c.-374G>A
NM_001354627.2:c.-374G>A
NM_001354628.2:c.453G>A
NM_001354629.2:c.354G>A
NM_001354630.2:c.453G>A
NP_000240.1:p.Thr151=
NP_000240.1:p.Thr151=
NP_001161089.1:p.Thr53=
NP_001245200.1:p.Thr151=
NP_001341549.1:p.Thr53=
NP_001341557.1:p.Thr151=
NP_001341558.1:p.Thr118=
NP_001341559.1:p.Thr151=
LRG_216t1:c.453G>A
LRG_216:g.18714G>A
LRG_216p1:p.Thr151=
NC_000003.11:g.37048554G>A
NM_000249.3:c.453G>A
p.T151T
p.Thr151Thr

Links:

dbSNP: rs369521379

NCBI 1000 Genomes Browser:

rs369521379

Molecular consequence:

NM_001167618.3:c.-271G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-179G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-271G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-271G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-179G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-179G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-271G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-271G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-271G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-364G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-477G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-477G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-374G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-282G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-374G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-374G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.453G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001167617.3:c.159G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001258271.2:c.453G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354620.2:c.159G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354628.2:c.453G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354629.2:c.354G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354630.2:c.453G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV001136377	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Apr 20, 2020)	unknown	clinical testing	Citation Link,
SCV002012375	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Aug 19, 2021)	germline	clinical testing	Citation Link,
SCV004195022	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001136377

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Apr 20, 2020)

unknown

clinical testing

Citation Link,

SCV002012375

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Aug 19, 2021)

germline

clinical testing

Citation Link,

SCV004195022

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 17, 2024)

unknown

clinical testing

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

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
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 Mendelics, SCV001136377.2

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

#	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

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002012375.2

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

Description

The MLH1 c.453G>A (p.Thr151=) synonymous change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/3-37048554-G-A). Algorithms that predict the impact of sequence changes on splicing indicate that this change may create or strengthen a splice site (PP3), but this prediction has not been confirmed by RNA studies. This variant has been reported in individuals with colorectal cancer and/or clinical features of Lynch syndrome (PMID: 26845104, 28449805, 33309985), individuals with other cancers (PMID: 31386297, 32634176), and in a tumor that demonstrated loss-of-heterozygosity of the wild-type allele (PMID: 29887214). It has also been reported in non-cancer controls (PMID: 33309985). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.

#	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

From Baylor Genetics, SCV004195022.2

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

#	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: Sep 29, 2024

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