NM_000249.4(MLH1):c.191A>G (p.Asn64Ser) AND Lynch syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 30, 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:: RCV000708912.5

Allele description [Variation Report for NM_000249.4(MLH1):c.191A>G (p.Asn64Ser)]

NM_000249.4(MLH1):c.191A>G (p.Asn64Ser)

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.191A>G (p.Asn64Ser)

Other names:

p.N64S:AAT>AGT

HGVS:

NC_000003.12:g.36996693A>G
NG_007109.2:g.8344A>G
NG_008418.1:g.1612T>C
NM_000249.4:c.191A>GMANE SELECT
NM_001167617.3:c.-99A>G
NM_001167618.3:c.-533A>G
NM_001167619.3:c.-441A>G
NM_001258271.2:c.191A>G
NM_001258273.2:c.-517+3030A>G
NM_001258274.3:c.-678A>G
NM_001354615.2:c.-436A>G
NM_001354616.2:c.-441A>G
NM_001354617.2:c.-533A>G
NM_001354618.2:c.-533A>G
NM_001354619.2:c.-533A>G
NM_001354620.2:c.-99A>G
NM_001354621.2:c.-626A>G
NM_001354622.2:c.-739A>G
NM_001354623.2:c.-723+2803A>G
NM_001354624.2:c.-636A>G
NM_001354625.2:c.-539A>G
NM_001354626.2:c.-636A>G
NM_001354627.2:c.-636A>G
NM_001354628.2:c.191A>G
NM_001354629.2:c.191A>G
NM_001354630.2:c.191A>G
NP_000240.1:p.Asn64Ser
NP_000240.1:p.Asn64Ser
NP_001245200.1:p.Asn64Ser
NP_001341557.1:p.Asn64Ser
NP_001341558.1:p.Asn64Ser
NP_001341559.1:p.Asn64Ser
LRG_216t1:c.191A>G
LRG_216:g.8344A>G
LRG_216p1:p.Asn64Ser
NC_000003.11:g.37038184A>G
NM_000249.3:c.191A>G
P40692:p.Asn64Ser

Protein change:

N64S

Links:

UniProtKB: P40692#VAR_004438; dbSNP: rs63750952

NCBI 1000 Genomes Browser:

rs63750952

Molecular consequence:

NM_001167617.3:c.-99A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-441A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-678A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-436A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-441A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-99A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-626A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-739A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-539A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3030A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2803A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

Recent activity

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protein MIZU-KUSSEI 1-like [Cucurbita pepo subsp. pepo]
protein MIZU-KUSSEI 1-like [Cucurbita pepo subsp. pepo]
gi|1333113306|ref|XP_023530791.1|

Protein
protein NEN1 [Cucumis sativus]
protein NEN1 [Cucumis sativus]
gi|778655989|ref|XP_011660176.1|

Protein
uncharacterized protein At5g01610-like isoform X2 [Cucumis melo]
uncharacterized protein At5g01610-like isoform X2 [Cucumis melo]
gi|2316582477|ref|XP_008446412.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000837994	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004835246	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9311737, 16736289, 17135187, 17510385, 21404117, 26552419, 28767289, 30504929, 31332305, 33471991, 36054288, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000837994

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Jul 2, 2018)

unknown

clinical testing

Citation Link,

SCV004835246

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 2023)

germline

clinical testing

PubMed (12)
[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	9	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations.

Wijnen J, Khan PM, Vasen H, van der Klift H, Mulder A, van Leeuwen-Cornelisse I, Bakker B, Losekoot M, Møller P, Fodde R.

Am J Hum Genet. 1997 Aug;61(2):329-35.

PubMed [citation]

PMID:: 9311737
PMCID:: PMC1715907

Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients.

Spaepen M, Vankeirsbilck B, Van Opstal S, Tejpar S, Van Cutsem E, Geboes K, Legius E, Matthijs G.

Fam Cancer. 2006;5(2):179-89.

PubMed [citation]

PMID:: 16736289

See all PubMed Citations (12)

Details of each submission

From Mendelics, SCV000837994.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004835246.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces asparagine with serine at codon 64 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). Functional studies have shown that this variant results in a partial loss of mismatch repair function and moderately reduced protein stability and binding ability to PMS2 protein (PMID: 17135187, 17510385, 21404117, 30504929, 36054288). This variant has been reported in individuals from Lynch syndrome families (PMID: 9311737, 16736289, 21404117). In one of these families, two affected siblings were carriers of this variant but their affected sister with microsatellite instability-high tumor did not carry this variant (PMID: 16736289). Three unaffected siblings from this family did not carry this variant. In another family, this variant co-occurred in trans with a different pathogenic variant in the MLH1 gene (PMID: 21404117, 31332305). This variant has also been reported in individuals affected with endometrial cancer (PMID: 26552419) or pancreatic cancer (PMID: 28767289). In a large breast cancer case-control study, this variant was observed in 6/60466 cases and 5/53461 unaffected controls (PMID: 33471991) This variant has been identified in 10/282844 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	108544	not provided	not provided		9	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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