NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 31, 2024
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:: RCV001181644.4

Allele description [Variation Report for NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro)]

NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro)

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.2074T>C (p.Ser692Pro)

Other names:

p.S692P:TCT>CCT

HGVS:

NC_000003.12:g.37048988T>C
NG_007109.2:g.60639T>C
NM_000249.4:c.2074T>CMANE SELECT
NM_001167617.3:c.1780T>C
NM_001167618.3:c.1351T>C
NM_001167619.3:c.1351T>C
NM_001258271.2:c.1896+1305T>C
NM_001258273.2:c.1351T>C
NM_001258274.3:c.1351T>C
NM_001354615.2:c.1351T>C
NM_001354616.2:c.1351T>C
NM_001354617.2:c.1351T>C
NM_001354618.2:c.1351T>C
NM_001354619.2:c.1351T>C
NM_001354620.2:c.1780T>C
NM_001354621.2:c.1051T>C
NM_001354622.2:c.1051T>C
NM_001354623.2:c.1051T>C
NM_001354624.2:c.1000T>C
NM_001354625.2:c.1000T>C
NM_001354626.2:c.1000T>C
NM_001354627.2:c.1000T>C
NM_001354628.2:c.1981T>C
NM_001354629.2:c.1975T>C
NM_001354630.2:c.1909T>C
NP_000240.1:p.Ser692Pro
NP_000240.1:p.Ser692Pro
NP_001161089.1:p.Ser594Pro
NP_001161090.1:p.Ser451Pro
NP_001161091.1:p.Ser451Pro
NP_001245202.1:p.Ser451Pro
NP_001245203.1:p.Ser451Pro
NP_001341544.1:p.Ser451Pro
NP_001341545.1:p.Ser451Pro
NP_001341546.1:p.Ser451Pro
NP_001341547.1:p.Ser451Pro
NP_001341548.1:p.Ser451Pro
NP_001341549.1:p.Ser594Pro
NP_001341550.1:p.Ser351Pro
NP_001341551.1:p.Ser351Pro
NP_001341552.1:p.Ser351Pro
NP_001341553.1:p.Ser334Pro
NP_001341554.1:p.Ser334Pro
NP_001341555.1:p.Ser334Pro
NP_001341556.1:p.Ser334Pro
NP_001341557.1:p.Ser661Pro
NP_001341558.1:p.Ser659Pro
NP_001341559.1:p.Ser637Pro
LRG_216t1:c.2074T>C
LRG_216:g.60639T>C
LRG_216p1:p.Ser692Pro
NC_000003.11:g.37090479T>C
NM_000249.3:c.2074T>C

Protein change:

S334P

Links:

dbSNP: rs587779957

NCBI 1000 Genomes Browser:

rs587779957

Molecular consequence:

NM_001258271.2:c.1896+1305T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.2074T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1981T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1975T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1909T>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
SCV001346833	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005134198	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 31, 2024)	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

SCV001346833

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 21, 2020)

germline

clinical testing

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

SCV005134198

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 31, 2024)

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

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

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001346833.2

#	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 serine with proline at codon 692 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 15713769). This variant has also been identified in 1/251112 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

From Ambry Genetics, SCV005134198.1

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

Description

The p.S692P variant (also known as c.2074T>C), located in coding exon 18 of the MLH1 gene, results from a T to C substitution at nucleotide position 2074. The serine at codon 692 is replaced by proline, an amino acid with similar properties. This variant was identified in an individual who met Amsterdam I criteria for Lynch syndrome but the tumor demonstrated normal MLH1 and MSH2 expression by immunohistochemistry (Casey G et al. JAMA, 2005 Feb;293:799-809). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant 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

Last Updated: Sep 29, 2024

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