NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 9, 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:: RCV003477466.1

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004220854	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Nov 9, 2022)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21404117, 16083711, 15849733, 17594722, 24362816, 21120944, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004220854

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(Nov 9, 2022)

unknown

clinical testing

PubMed (7)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.

Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lönnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, Gerdes AM, Peltomäki P, Kohonen-Ccorish M, Mangold E, Macrae F, Greenblatt M, de la Chapelle A, Nyström M.

Gastroenterology. 2005 Aug;129(2):537-49.

PubMed [citation]

PMID:: 16083711

See all PubMed Citations (7)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220854.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome fulfilling Amsterdam 1 criteria (PMIDs: 15849733 (2005), 16083711 (2005), and 21120944 (2011)), with tumors that display loss of MLH1 expression and increased microsatellite instability (PMIDs: 15849733 (2005), 16083711 (2005), and 21404117 (2011)). Functional studies show the variant is damaging to protein function by decreasing MLH1 expression and causing improper nuclear localization (PMIDs: 16083711 (2005) and 21120944 (2011)). Additionally, multifactorial likelihood analysis predicts a high probability that this variant is pathogenic (PMID: 243362816 (2014)). Based on the available information, this variant is classified as likely pathogenic.

#	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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