NM_000249.4(MLH1):c.974G>A (p.Arg325Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Jun 27, 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:: RCV000163500.8

Allele description [Variation Report for NM_000249.4(MLH1):c.974G>A (p.Arg325Gln)]

NM_000249.4(MLH1):c.974G>A (p.Arg325Gln)

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.974G>A (p.Arg325Gln)

HGVS:

NC_000003.12:g.37020399G>A
NG_007109.2:g.32050G>A
NM_000249.4:c.974G>AMANE SELECT
NM_001167617.3:c.680G>A
NM_001167618.3:c.251G>A
NM_001167619.3:c.251G>A
NM_001258271.2:c.974G>A
NM_001258273.2:c.251G>A
NM_001258274.3:c.251G>A
NM_001354615.2:c.251G>A
NM_001354616.2:c.251G>A
NM_001354617.2:c.251G>A
NM_001354618.2:c.251G>A
NM_001354619.2:c.251G>A
NM_001354620.2:c.680G>A
NM_001354621.2:c.-50G>A
NM_001354622.2:c.-50G>A
NM_001354623.2:c.-50G>A
NM_001354624.2:c.-36-5238G>A
NM_001354625.2:c.-36-5238G>A
NM_001354626.2:c.-36-5238G>A
NM_001354627.2:c.-36-5238G>A
NM_001354628.2:c.974G>A
NM_001354629.2:c.875G>A
NM_001354630.2:c.974G>A
NP_000240.1:p.Arg325Gln
NP_000240.1:p.Arg325Gln
NP_001161089.1:p.Arg227Gln
NP_001161090.1:p.Arg84Gln
NP_001161091.1:p.Arg84Gln
NP_001245200.1:p.Arg325Gln
NP_001245202.1:p.Arg84Gln
NP_001245203.1:p.Arg84Gln
NP_001341544.1:p.Arg84Gln
NP_001341545.1:p.Arg84Gln
NP_001341546.1:p.Arg84Gln
NP_001341547.1:p.Arg84Gln
NP_001341548.1:p.Arg84Gln
NP_001341549.1:p.Arg227Gln
NP_001341557.1:p.Arg325Gln
NP_001341558.1:p.Arg292Gln
NP_001341559.1:p.Arg325Gln
LRG_216t1:c.974G>A
LRG_216:g.32050G>A
LRG_216p1:p.Arg325Gln
NC_000003.11:g.37061890G>A
NM_000249.3:c.974G>A
P40692:p.Arg325Gln
p.R325Q

Protein change:

R227Q

Links:

UniProtKB: P40692#VAR_012917; dbSNP: rs63750268

NCBI 1000 Genomes Browser:

rs63750268

Molecular consequence:

NM_001354621.2:c.-50G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-50G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-50G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.875G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.974G>A - 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
SCV000214058	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Oct 30, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000910960	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 4, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528791	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely benign (Jun 27, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214058

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Oct 30, 2018)

germline

clinical testing

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

Citation Link,

SCV000910960

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Mar 4, 2016)

germline

clinical testing

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

SCV002528791

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely benign
(Jun 27, 2021)

germline

curation

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, curation

Citations

PubMed

Comprehensive functional assessment of MLH1 variants of unknown significance.

Borràs E, Pineda M, Brieger A, Hinrichsen I, Gómez C, Navarro M, Balmaña J, Ramón y Cajal T, Torres A, Brunet J, Blanco I, Plotz G, Lázaro C, Capellá G.

Hum Mutat. 2012 Nov;33(11):1576-88. doi: 10.1002/humu.22142. Epub 2012 Jul 12. Erratum in: Hum Mutat. 2013 Jan;34(1):274.

PubMed [citation]

PMID:: 22736432

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, SCV000214058.7

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000910960.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002528791.1

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

#	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: Oct 13, 2024

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