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NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 29, 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:
RCV000574309.5

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 cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000673841Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Dec 29, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.

Mangold E, Pagenstecher C, Friedl W, Fischer HP, Merkelbach-Bruse S, Ohlendorf M, Friedrichs N, Aretz S, Buettner R, Propping P, Mathiak M.

J Pathol. 2005 Dec;207(4):385-95.

PubMed [citation]
PMID:
16216036
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000673841.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The c.1835_1837delTTG variant (also known as p.V612del) is located in coding exon 16 of the MLH1 gene. This variant results from an in-frame TTG deletion at nucleotide positions 1835 to 1837. This results in the in-frame deletion of a valine at codon 612. This alteration has been reported in an individual with a family history that met Amsterdam I criteria and who was diagnosed with a MSI-H colorectal cancer that displayed loss of MLH1 expression on immunohistochemistry (Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49; Mangold E et al. J Pathol. 2005 Dec;207(4):385-95; Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84). Functional studies of this alteration showed decreased expression in 293T cells and aberrant nuclear localization (Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49). This alteration has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on internal structural analysis, this alteration is expected to result in substantial structural rearrangement in a helix of the dimerization domain where other pathogenic missense alterations are present. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024