NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 16, 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:: RCV001201372.6

Allele description [Variation Report for NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del)]

NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del)

HGVS:

NC_000003.11:g.37089110_37089112del
NC_000003.12:g.37047619TTG[1]
NG_007109.2:g.59270TTG[1]
NM_000249.4:c.1832TTG[1]MANE SELECT
NM_001167617.3:c.1538TTG[1]
NM_001167618.3:c.1109TTG[1]
NM_001167619.3:c.1109TTG[1]
NM_001258271.2:c.1832TTG[1]
NM_001258273.2:c.1109TTG[1]
NM_001258274.3:c.1109TTG[1]
NM_001354615.2:c.1109TTG[1]
NM_001354616.2:c.1109TTG[1]
NM_001354617.2:c.1109TTG[1]
NM_001354618.2:c.1109TTG[1]
NM_001354619.2:c.1109TTG[1]
NM_001354620.2:c.1538TTG[1]
NM_001354621.2:c.809TTG[1]
NM_001354622.2:c.809TTG[1]
NM_001354623.2:c.809TTG[1]
NM_001354624.2:c.758TTG[1]
NM_001354625.2:c.758TTG[1]
NM_001354626.2:c.758TTG[1]
NM_001354627.2:c.758TTG[1]
NM_001354628.2:c.1832TTG[1]
NM_001354629.2:c.1733TTG[1]
NM_001354630.2:c.1732-895_1732-893del
NP_000240.1:p.Val612del
NP_001161089.1:p.Val514del
NP_001161090.1:p.Val371del
NP_001161091.1:p.Val371del
NP_001245200.1:p.Val612del
NP_001245202.1:p.Val371del
NP_001245203.1:p.Val371del
NP_001341544.1:p.Val371del
NP_001341545.1:p.Val371del
NP_001341546.1:p.Val371del
NP_001341547.1:p.Val371del
NP_001341548.1:p.Val371del
NP_001341549.1:p.Val514del
NP_001341550.1:p.Val271del
NP_001341551.1:p.Val271del
NP_001341552.1:p.Val271del
NP_001341553.1:p.Val254del
NP_001341554.1:p.Val254del
NP_001341555.1:p.Val254del
NP_001341556.1:p.Val254del
NP_001341557.1:p.Val612del
NP_001341558.1:p.Val579del
LRG_216:g.59270TTG[1]
NC_000003.11:g.37089110TTG[1]
NC_000003.11:g.37089110_37089112del
NC_000003.11:g.37089110_37089112delTTG
NM_000249.3:c.1835_1837delTTG

Protein change:

V254del

Links:

dbSNP: rs63750486

NCBI 1000 Genomes Browser:

rs63750486

Molecular consequence:

NM_000249.4:c.1832TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167617.3:c.1538TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167618.3:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167619.3:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258271.2:c.1832TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258273.2:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258274.3:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354615.2:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354616.2:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354617.2:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354618.2:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354619.2:c.1109TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354620.2:c.1538TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354621.2:c.809TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354622.2:c.809TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354623.2:c.809TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354624.2:c.758TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354625.2:c.758TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354626.2:c.758TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354627.2:c.758TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354628.2:c.1832TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354629.2:c.1733TTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354630.2:c.1732-895_1732-893del - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000543647	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15849733, 21404117, 24362816, 16083711, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543647

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 16, 2023)

germline

clinical testing

PubMed (5)
[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

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

PMID:: 15849733

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543647.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant, c.1835_1837del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Val612del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 16083711, 21404117; Invitae). ClinVar contains an entry for this variant (Variation ID: 89900). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies have shown that this variant affects MLH1 function (PMID: 16083711). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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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