NM_000249.4(MLH1):c.4T>G (p.Ser2Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 5, 2021
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:: RCV002348491.2

Allele description [Variation Report for NM_000249.4(MLH1):c.4T>G (p.Ser2Ala)]

NM_000249.4(MLH1):c.4T>G (p.Ser2Ala)

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.4T>G (p.Ser2Ala)

HGVS:

NC_000003.12:g.36993551T>G
NG_007109.2:g.5202T>G
NG_008418.1:g.4754A>C
NM_000249.4:c.4T>GMANE SELECT
NM_001167617.3:c.-513T>G
NM_001167618.3:c.-942T>G
NM_001167619.3:c.-855T>G
NM_001258271.2:c.4T>G
NM_001258273.2:c.-629T>G
NM_001258274.3:c.-1092T>G
NM_001354615.2:c.-623T>G
NM_001354616.2:c.-623T>G
NM_001354617.2:c.-715T>G
NM_001354618.2:c.-947T>G
NM_001354619.2:c.-1071T>G
NM_001354620.2:c.-281T>G
NM_001354621.2:c.-1040T>G
NM_001354622.2:c.-1153T>G
NM_001354623.2:c.-1062T>G
NM_001354624.2:c.-823T>G
NM_001354625.2:c.-721T>G
NM_001354626.2:c.-818T>G
NM_001354627.2:c.-1050T>G
NM_001354628.2:c.4T>G
NM_001354629.2:c.4T>G
NM_001354630.2:c.4T>G
NP_000240.1:p.Ser2Ala
NP_001245200.1:p.Ser2Ala
NP_001341557.1:p.Ser2Ala
NP_001341558.1:p.Ser2Ala
NP_001341559.1:p.Ser2Ala
LRG_216t1:c.4T>G
LRG_216:g.5202T>G
NC_000003.11:g.37035042T>G
NM_000249.3:c.4T>G

Protein change:

S2A

Links:

dbSNP: rs1448308275

NCBI 1000 Genomes Browser:

rs1448308275

Molecular consequence:

NM_001167617.3:c.-513T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-942T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-855T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-629T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1092T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-623T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-623T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-715T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-947T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1071T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-281T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1040T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1153T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1062T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-823T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-721T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-818T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1050T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.4T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.4T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.4T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.4T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.4T>G - 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
SCV002645451	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 5, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30521064, 31830689, 32661327 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002645451

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 5, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature.

Zhang L, Bhaskaran SP, Huang T, Dong H, Chandratre K, Wu X, Qin Z, Wang X, Cao W, Chen T, Lynch H, Wang SM.

Eur J Cancer. 2020 Jan;125:12-21. doi: 10.1016/j.ejca.2019.11.004. Epub 2019 Dec 9.

PubMed [citation]

PMID:: 31830689

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002645451.2

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

Description

The p.S2A variant (also known as c.4T>G), located in coding exon 1 of the MLH1 gene, results from a T to G substitution at nucleotide position 4. The serine at codon 2 is replaced by alanine, an amino acid with similar properties. This alteration was identified in a 29 year old female diagnosed with colorectal cancer whose tumor showed loss of the MLH1 and PMS2 proteins on immunohistochemistry (IHC) (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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