NM_000249.4(MLH1):c.1754T>C (p.Leu585Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 3, 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:: RCV000573430.3

Allele description [Variation Report for NM_000249.4(MLH1):c.1754T>C (p.Leu585Pro)]

NM_000249.4(MLH1):c.1754T>C (p.Leu585Pro)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1754T>C (p.Leu585Pro)

HGVS:

NC_000003.12:g.37047541T>C
NG_007109.2:g.59192T>C
NM_000249.4:c.1754T>CMANE SELECT
NM_001167617.3:c.1460T>C
NM_001167618.3:c.1031T>C
NM_001167619.3:c.1031T>C
NM_001258271.2:c.1754T>C
NM_001258273.2:c.1031T>C
NM_001258274.3:c.1031T>C
NM_001354615.2:c.1031T>C
NM_001354616.2:c.1031T>C
NM_001354617.2:c.1031T>C
NM_001354618.2:c.1031T>C
NM_001354619.2:c.1031T>C
NM_001354620.2:c.1460T>C
NM_001354621.2:c.731T>C
NM_001354622.2:c.731T>C
NM_001354623.2:c.731T>C
NM_001354624.2:c.680T>C
NM_001354625.2:c.680T>C
NM_001354626.2:c.680T>C
NM_001354627.2:c.680T>C
NM_001354628.2:c.1754T>C
NM_001354629.2:c.1655T>C
NM_001354630.2:c.1732-976T>C
NP_000240.1:p.Leu585Pro
NP_000240.1:p.Leu585Pro
NP_001161089.1:p.Leu487Pro
NP_001161090.1:p.Leu344Pro
NP_001161091.1:p.Leu344Pro
NP_001245200.1:p.Leu585Pro
NP_001245202.1:p.Leu344Pro
NP_001245203.1:p.Leu344Pro
NP_001341544.1:p.Leu344Pro
NP_001341545.1:p.Leu344Pro
NP_001341546.1:p.Leu344Pro
NP_001341547.1:p.Leu344Pro
NP_001341548.1:p.Leu344Pro
NP_001341549.1:p.Leu487Pro
NP_001341550.1:p.Leu244Pro
NP_001341551.1:p.Leu244Pro
NP_001341552.1:p.Leu244Pro
NP_001341553.1:p.Leu227Pro
NP_001341554.1:p.Leu227Pro
NP_001341555.1:p.Leu227Pro
NP_001341556.1:p.Leu227Pro
NP_001341557.1:p.Leu585Pro
NP_001341558.1:p.Leu552Pro
LRG_216t1:c.1754T>C
LRG_216:g.59192T>C
LRG_216p1:p.Leu585Pro
NC_000003.11:g.37089032T>C
NM_000249.3:c.1754T>C

Protein change:

L227P

Links:

dbSNP: rs267607865

NCBI 1000 Genomes Browser:

rs267607865

Molecular consequence:

NM_001354630.2:c.1732-976T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1754T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1460T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1754T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1460T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.731T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.731T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.731T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.680T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.680T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.680T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.680T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1754T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1655T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000669605	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669605

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 3, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.

Jiang W, Cai MY, Li SY, Bei JX, Wang F, Hampel H, Ling YH, Frayling IM, Sinicrope FA, Rodriguez-Bigas MA, Dignam JJ, Kerr DJ, Rosell R, Mao M, Li JB, Guo YM, Wu XY, Kong LH, Tang JH, Wu XD, Li CF, Chen JR, et al.

Int J Cancer. 2019 May 1;144(9):2161-2168. doi: 10.1002/ijc.32044. Epub 2019 Jan 9.

PubMed [citation]

PMID:: 30521064

Details of each submission

From Ambry Genetics, SCV000669605.5

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

Description

The p.L585P variant (also known as c.1754T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1754. The leucine at codon 585 is replaced by proline, an amino acid with similar properties. This variant has been reported in a female proband who did not meet Amsterdam criteria (AC) or Bethesda guidelines for Lynch syndrome, but did have loss of MLH1 protein expression in her colorectal tumor by immunohistochemistry (IHC) (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This variant was also identified in a proband whose family history met ACII for Lynch syndrome and colorectal tumor demonstrated loss of both MLH1/PMS2 protein expression by IHC (Ambry internal data). Based on internal structural analysis, L585P results in decreased structural stability (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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: Sep 29, 2024

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