NM_000249.4(MLH1):c.506C>T (p.Pro169Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000218502.9

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 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
SCV000277501	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 15, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16237216, 26333163 Citation Link,
SCV001342529	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 18, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16237216, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000277501

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 15, 2022)

germline

clinical testing

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

Citation Link,

SCV001342529

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 18, 2023)

germline

clinical testing

PubMed (2)
[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

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

Tumor microsatellite instability in early onset gastric cancer.

Bacani J, Zwingerman R, Di Nicola N, Spencer S, Wegrynowski T, Mitchell K, Hay K, Redston M, Holowaty E, Huntsman D, Pollett A, Riddell R, Gallinger S.

J Mol Diagn. 2005 Oct;7(4):465-77.

PubMed [citation]

PMID:: 16237216
PMCID:: PMC1888489

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000277501.7

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

Description

The p.P169L variant (also known as c.506C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 506. The proline at codon 169 is replaced by leucine, an amino acid with similar properties. This alteration was identified in a cohort of Iranian patients whose personal and family cancer history meets the Amsterdam criteria (Salehi M et al. J Sci I Iran. 2009; 20(1):7-12). This variant was reportedly detected in conjunction (phase unknown) with a pathogenic mutation in MLH1 in a 35-year-old male with mixed proximal gastric cancer (Bacani J et al. J Mol Diagn. 2005 Oct;7:465-77). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV001342529.3

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

Description

This missense variant replaces proline with leucine at codon 169 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in trans with a pathogenic MLH1 variant in an individual affected with gastric cancer (PMID: 16237216) and in a suspected hereditary nonpolyposis colorectal cancer family (Salehi, 2008). This variant has been identified in 1/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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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