NM_000249.4(MLH1):c.2166dup (p.Ala723fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 29, 2022
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:: RCV002858719.3

Allele description [Variation Report for NM_000249.4(MLH1):c.2166dup (p.Ala723fs)]

NM_000249.4(MLH1):c.2166dup (p.Ala723fs)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2166dup (p.Ala723fs)

HGVS:

NC_000003.12:g.37050548dup
NG_007109.2:g.62199dup
NM_000249.4:c.2166dupMANE SELECT
NM_001167617.3:c.1872dup
NM_001167618.3:c.1443dup
NM_001167619.3:c.1443dup
NM_001258271.2:c.1959dup
NM_001258273.2:c.1443dup
NM_001258274.3:c.1443dup
NM_001354615.2:c.1443dup
NM_001354616.2:c.1443dup
NM_001354617.2:c.1443dup
NM_001354618.2:c.1443dup
NM_001354619.2:c.1443dup
NM_001354620.2:c.1872dup
NM_001354621.2:c.1143dup
NM_001354622.2:c.1143dup
NM_001354623.2:c.1143dup
NM_001354624.2:c.1092dup
NM_001354625.2:c.1092dup
NM_001354626.2:c.1092dup
NM_001354627.2:c.1092dup
NM_001354628.2:c.2073dup
NM_001354629.2:c.2067dup
NM_001354630.2:c.2001dup
NP_000240.1:p.Ala723Serfs
NP_000240.1:p.Ala723fs
NP_001161089.1:p.Ala625fs
NP_001161090.1:p.Ala482fs
NP_001161091.1:p.Ala482fs
NP_001245200.1:p.Ala654fs
NP_001245202.1:p.Ala482fs
NP_001245203.1:p.Ala482fs
NP_001341544.1:p.Ala482fs
NP_001341545.1:p.Ala482fs
NP_001341546.1:p.Ala482fs
NP_001341547.1:p.Ala482fs
NP_001341548.1:p.Ala482fs
NP_001341549.1:p.Ala625fs
NP_001341550.1:p.Ala382fs
NP_001341551.1:p.Ala382fs
NP_001341552.1:p.Ala382fs
NP_001341553.1:p.Ala365fs
NP_001341554.1:p.Ala365fs
NP_001341555.1:p.Ala365fs
NP_001341556.1:p.Ala365fs
NP_001341557.1:p.Ala692fs
NP_001341558.1:p.Ala690fs
NP_001341559.1:p.Ala668fs
LRG_216t1:c.2166dup
LRG_216:g.62199dup
LRG_216p1:p.Ala723Serfs
NC_000003.11:g.37092036_37092037insA
NC_000003.11:g.37092039dup
NM_000249.3:c.2166dup

Protein change:

A365fs

Molecular consequence:

NM_000249.4:c.2166dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1872dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1959dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1443dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1872dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1143dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1143dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1143dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1092dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1092dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1092dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1092dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2073dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2067dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.2001dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003232388	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 29, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8797773, 18566915, 18931482, 24802709, 27295708, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003232388

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 29, 2022)

germline

clinical testing

PubMed (6)
[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

Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer.

Han HJ, Yuan Y, Ku JL, Oh JH, Won YJ, Kang KJ, Kim KY, Kim S, Kim CY, Kim JP, Oh NG, Lee KH, Choe KJ, Nakamura Y, Park JG.

J Natl Cancer Inst. 1996 Sep 18;88(18):1317-9. No abstract available.

PubMed [citation]

PMID:: 8797773

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003232388.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala723Serfs*10) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the MLH1 protein. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 29, 2024

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