NM_000249.4(MLH1):c.776T>C (p.Leu259Ser) AND Hereditary cancer-predisposing syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 16, 2020
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:: RCV000562377.6

Allele description

NM_000249.4(MLH1):c.776T>C (p.Leu259Ser)

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.776T>C (p.Leu259Ser)

Other names:

p.L259S:TTA>TCA

HGVS:

NC_000003.12:g.37014530T>C
NG_007109.2:g.26181T>C
NM_000249.4:c.776T>CMANE SELECT
NM_001167617.3:c.482T>C
NM_001167618.3:c.53T>C
NM_001167619.3:c.53T>C
NM_001258271.2:c.776T>C
NM_001258273.2:c.53T>C
NM_001258274.3:c.53T>C
NM_001354615.2:c.53T>C
NM_001354616.2:c.53T>C
NM_001354617.2:c.53T>C
NM_001354618.2:c.53T>C
NM_001354619.2:c.53T>C
NM_001354620.2:c.482T>C
NM_001354621.2:c.-140+2431T>C
NM_001354622.2:c.-154T>C
NM_001354623.2:c.-154T>C
NM_001354624.2:c.-51T>C
NM_001354625.2:c.-51T>C
NM_001354626.2:c.-51T>C
NM_001354627.2:c.-51T>C
NM_001354628.2:c.776T>C
NM_001354629.2:c.677T>C
NM_001354630.2:c.776T>C
NP_000240.1:p.Leu259Ser
NP_000240.1:p.Leu259Ser
NP_001161089.1:p.Leu161Ser
NP_001161090.1:p.Leu18Ser
NP_001161091.1:p.Leu18Ser
NP_001245200.1:p.Leu259Ser
NP_001245202.1:p.Leu18Ser
NP_001245203.1:p.Leu18Ser
NP_001341544.1:p.Leu18Ser
NP_001341545.1:p.Leu18Ser
NP_001341546.1:p.Leu18Ser
NP_001341547.1:p.Leu18Ser
NP_001341548.1:p.Leu18Ser
NP_001341549.1:p.Leu161Ser
NP_001341557.1:p.Leu259Ser
NP_001341558.1:p.Leu226Ser
NP_001341559.1:p.Leu259Ser
LRG_216t1:c.776T>C
LRG_216:g.26181T>C
LRG_216p1:p.Leu259Ser
NC_000003.11:g.37056021T>C
NM_000249.3:c.776T>C

Protein change:

L161S

Links:

dbSNP: rs56250509

NCBI 1000 Genomes Browser:

rs56250509

Molecular consequence:

NM_001354622.2:c.-154T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-154T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-51T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-51T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-51T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-51T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-140+2431T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.482T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.482T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.677T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.776T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000669540	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (3/2017))	Uncertain significance (Nov 15, 2018)	germline	clinical testing	Citation Link,
SCV000684863	Color Health, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 16, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669540

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (3/2017))

Uncertain significance
(Nov 15, 2018)

germline

clinical testing

Citation Link,

SCV000684863

Color Health, Inc

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 16, 2020)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000669540.3

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

Description

The p.L259S variant (also known as c.776T>C), located in coding exon 9 of the MLH1 gene, results from a T to C substitution at nucleotide position 776. The leucine at codon 259 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Health, Inc, SCV000684863.4

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

Description

This missense variant replaces leucine with serine at codon 259 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant protein retains the ability to bind PMS2 in a yeast two-hybrid assay (PMID: 22252508). This variant has been observed in at least two unrelated individuals with a likely pathogenic MLH1 covariant, however, the in cis or in trans phasing of the two variants is unknown (UMD record ID: 1120; Color internal data). This variant has been identified in 5/250852 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: Apr 23, 2022

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