NM_000249.4(MLH1):c.541G>A (p.Gly181Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 3, 2021
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:: RCV000482251.10

Allele description [Variation Report for NM_000249.4(MLH1):c.541G>A (p.Gly181Ser)]

NM_000249.4(MLH1):c.541G>A (p.Gly181Ser)

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.541G>A (p.Gly181Ser)

HGVS:

NC_000003.12:g.37008901G>A
NG_007109.2:g.20552G>A
NM_000249.4:c.541G>AMANE SELECT
NM_001167617.3:c.247G>A
NM_001167618.3:c.-183G>A
NM_001167619.3:c.-179+1838G>A
NM_001258271.2:c.541G>A
NM_001258273.2:c.-183G>A
NM_001258274.3:c.-183G>A
NM_001354615.2:c.-179+1838G>A
NM_001354616.2:c.-179+1838G>A
NM_001354617.2:c.-183G>A
NM_001354618.2:c.-183G>A
NM_001354619.2:c.-183G>A
NM_001354620.2:c.247G>A
NM_001354621.2:c.-276G>A
NM_001354622.2:c.-389G>A
NM_001354623.2:c.-389G>A
NM_001354624.2:c.-286G>A
NM_001354625.2:c.-282+1838G>A
NM_001354626.2:c.-286G>A
NM_001354627.2:c.-286G>A
NM_001354628.2:c.541G>A
NM_001354629.2:c.442G>A
NM_001354630.2:c.541G>A
NP_000240.1:p.Gly181Ser
NP_000240.1:p.Gly181Ser
NP_001161089.1:p.Gly83Ser
NP_001245200.1:p.Gly181Ser
NP_001341549.1:p.Gly83Ser
NP_001341557.1:p.Gly181Ser
NP_001341558.1:p.Gly148Ser
NP_001341559.1:p.Gly181Ser
LRG_216t1:c.541G>A
LRG_216:g.20552G>A
LRG_216p1:p.Gly181Ser
NC_000003.11:g.37050392G>A
NM_000249.3:c.541G>A

Protein change:

G148S

Links:

dbSNP: rs1064795694

NCBI 1000 Genomes Browser:

rs1064795694

Molecular consequence:

NM_001167618.3:c.-183G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-183G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-183G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-183G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-183G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-183G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-276G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-389G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-389G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-286G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-286G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-286G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-179+1838G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-179+1838G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-179+1838G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-282+1838G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.247G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.541G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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SRP151686 (185)
SRA
acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase [Paracocc...
acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase [Paracoccus tegillarcae]
gi|1317055012|gnl|PRJNA417897|CUV01 5|gb|AUH34870.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000571728	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Sep 18, 2016)	germline	clinical testing	Citation Link,
SCV002009358	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	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

SCV000571728

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Sep 18, 2016)

germline

clinical testing

Citation Link,

SCV002009358

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 3, 2021)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	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

Details of each submission

From GeneDx, SCV000571728.4

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

Description

This variant is denoted MLH1 c.541G>A at the cDNA level, p.Gly181Ser (G181S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Gly181Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly181Ser occurs at a position that is conserved in mammals and is not located in a known functional domain (Raevaara 2005, Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Gly181Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009358.3

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

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

Last Updated: Sep 16, 2024

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