NM_000249.4(MLH1):c.506C>T (p.Pro169Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 30, 2024
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:: RCV000524304.8

Allele description [Variation Report for NM_000249.4(MLH1):c.506C>T (p.Pro169Leu)]

NM_000249.4(MLH1):c.506C>T (p.Pro169Leu)

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.506C>T (p.Pro169Leu)

HGVS:

NC_000003.12:g.37008866C>T
NG_007109.2:g.20517C>T
NM_000249.4:c.506C>TMANE SELECT
NM_001167617.3:c.212C>T
NM_001167618.3:c.-218C>T
NM_001167619.3:c.-179+1803C>T
NM_001258271.2:c.506C>T
NM_001258273.2:c.-218C>T
NM_001258274.3:c.-218C>T
NM_001354615.2:c.-179+1803C>T
NM_001354616.2:c.-179+1803C>T
NM_001354617.2:c.-218C>T
NM_001354618.2:c.-218C>T
NM_001354619.2:c.-218C>T
NM_001354620.2:c.212C>T
NM_001354621.2:c.-311C>T
NM_001354622.2:c.-424C>T
NM_001354623.2:c.-424C>T
NM_001354624.2:c.-321C>T
NM_001354625.2:c.-282+1803C>T
NM_001354626.2:c.-321C>T
NM_001354627.2:c.-321C>T
NM_001354628.2:c.506C>T
NM_001354629.2:c.407C>T
NM_001354630.2:c.506C>T
NP_000240.1:p.Pro169Leu
NP_000240.1:p.Pro169Leu
NP_001161089.1:p.Pro71Leu
NP_001245200.1:p.Pro169Leu
NP_001341549.1:p.Pro71Leu
NP_001341557.1:p.Pro169Leu
NP_001341558.1:p.Pro136Leu
NP_001341559.1:p.Pro169Leu
LRG_216t1:c.506C>T
LRG_216:g.20517C>T
LRG_216p1:p.Pro169Leu
NC_000003.11:g.37050357C>T
NM_000249.3:c.506C>T

Protein change:

P136L

Links:

dbSNP: rs63750834

NCBI 1000 Genomes Browser:

rs63750834

Molecular consequence:

NM_001167618.3:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-218C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-311C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-424C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-424C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-321C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-321C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-321C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-179+1803C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-179+1803C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-179+1803C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-282+1803C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.212C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.212C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.407C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000543524	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 30, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31391288, 26333163, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543524

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 30, 2024)

germline

clinical testing

PubMed (3)
[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

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity.

Li S, Qian D, Thompson BA, Gutierrez S, Wu S, Pesaran T, LaDuca H, Lu HM, Chao EC, Black MH.

J Med Genet. 2020 Jan;57(1):62-69. doi: 10.1136/jmedgenet-2019-106096. Epub 2019 Aug 7.

PubMed [citation]

PMID:: 31391288

Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2.

Niroula A, Vihinen M.

Hum Mutat. 2015 Dec;36(12):1128-34. doi: 10.1002/humu.22900. Epub 2015 Sep 22.

PubMed [citation]

PMID:: 26333163

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543524.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 169 of the MLH1 protein (p.Pro169Leu). This variant is present in population databases (rs63750834, gnomAD 0.0009%). This missense change has been observed in individual(s) with suspected Lynch syndrome (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 90251). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). Studies have shown this missense change is associated with skipping of exon 6, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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