NM_000249.4(MLH1):c.2248_2249del (p.Tyr750fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 12, 2021
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:: RCV000165077.4

Allele description [Variation Report for NM_000249.4(MLH1):c.2248_2249del (p.Tyr750fs)]

NM_000249.4(MLH1):c.2248_2249del (p.Tyr750fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2248_2249del (p.Tyr750fs)

HGVS:

NC_000003.12:g.37050628TA[1]
NG_007109.2:g.62279TA[1]
NG_053016.1:g.131187TA[1]
NM_000249.4:c.2248_2249delMANE SELECT
NM_001167617.3:c.1954_1955del
NM_001167618.3:c.1525_1526del
NM_001167619.3:c.1525_1526del
NM_001258271.2:c.2041_2042del
NM_001258273.2:c.1525_1526del
NM_001258274.3:c.1525_1526del
NM_001354615.2:c.1525_1526del
NM_001354616.2:c.1525_1526del
NM_001354617.2:c.1525_1526del
NM_001354618.2:c.1525_1526del
NM_001354619.2:c.1525_1526del
NM_001354620.2:c.1954_1955del
NM_001354621.2:c.1225_1226del
NM_001354622.2:c.1225_1226del
NM_001354623.2:c.1225_1226del
NM_001354624.2:c.1174_1175del
NM_001354625.2:c.1174_1175del
NM_001354626.2:c.1174_1175del
NM_001354627.2:c.1174_1175del
NM_001354628.2:c.2155_2156del
NM_001354629.2:c.2149_2150del
NM_001354630.2:c.2083_2084del
NP_000240.1:p.Tyr750fs
NP_001161089.1:p.Tyr652fs
NP_001161090.1:p.Tyr509fs
NP_001161091.1:p.Tyr509fs
NP_001245200.1:p.Tyr681fs
NP_001245202.1:p.Tyr509fs
NP_001245203.1:p.Tyr509fs
NP_001341544.1:p.Tyr509fs
NP_001341545.1:p.Tyr509fs
NP_001341546.1:p.Tyr509fs
NP_001341547.1:p.Tyr509fs
NP_001341548.1:p.Tyr509fs
NP_001341549.1:p.Tyr652fs
NP_001341550.1:p.Tyr409fs
NP_001341551.1:p.Tyr409fs
NP_001341552.1:p.Tyr409fs
NP_001341553.1:p.Tyr392fs
NP_001341554.1:p.Tyr392fs
NP_001341555.1:p.Tyr392fs
NP_001341556.1:p.Tyr392fs
NP_001341557.1:p.Tyr719fs
NP_001341558.1:p.Tyr717fs
NP_001341559.1:p.Tyr695fs
LRG_216:g.62279TA[1]
NC_000003.11:g.37092119TA[1]
NM_000249.3:c.2248_2249delTA
p.Y750QFS*4

Protein change:

Y392fs

Links:

dbSNP: rs786202326

NCBI 1000 Genomes Browser:

rs786202326

Molecular consequence:

NM_000249.4:c.2248_2249del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1954_1955del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.2041_2042del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1525_1526del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1954_1955del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1225_1226del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1225_1226del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1225_1226del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1174_1175del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1174_1175del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1174_1175del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1174_1175del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2155_2156del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2149_2150del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.2083_2084del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215779	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 12, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23435383, 26249686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215779

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 12, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site.

Gueneau E, Dherin C, Legrand P, Tellier-Lebegue C, Gilquin B, Bonnesoeur P, Londino F, Quemener C, Le Du MH, Márquez JA, Moutiez M, Gondry M, Boiteux S, Charbonnier JB.

Nat Struct Mol Biol. 2013 Apr;20(4):461-8. doi: 10.1038/nsmb.2511. Epub 2013 Feb 24.

PubMed [citation]

PMID:: 23435383

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome.

Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J.

Acta Crystallogr F Struct Biol Commun. 2015 Aug;71(Pt 8):981-5. doi: 10.1107/S2053230X15010183. Epub 2015 Jul 28.

PubMed [citation]

PMID:: 26249686
PMCID:: PMC4528928

Details of each submission

From Ambry Genetics, SCV000215779.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.2248_2249delTA variant, located in coding exon 19 of the MLH1 gene, results from a deletion of two nucleotides at positions 2248 to 2249 causing a translational frameshift with a predicted alternate stop codon (p.Y750QFS*4). Frameshifts are typically deleterious in nature, but this frameshift occurs at the 3' terminus of MLH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 7 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, structural analysis suggests that this alteration perturbs a known functional domain responsible for binding to as well as stabilizing PMS2 and removes a cysteine residue shown to be involved in metal binding as part of a functional domain in PMS2 (Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr;20:461-8; Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5). Based on the majority of available evidence to date, this variant is likely to be 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: May 1, 2024

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