NM_000249.4(MLH1):c.1682A>G (p.Tyr561Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 26, 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:: RCV000568554.7

Allele description [Variation Report for NM_000249.4(MLH1):c.1682A>G (p.Tyr561Cys)]

NM_000249.4(MLH1):c.1682A>G (p.Tyr561Cys)

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.1682A>G (p.Tyr561Cys)

Other names:

p.Tyr561Cys

HGVS:

NC_000003.12:g.37042282A>G
NG_007109.2:g.53933A>G
NM_000249.4:c.1682A>GMANE SELECT
NM_001167617.3:c.1388A>G
NM_001167618.3:c.959A>G
NM_001167619.3:c.959A>G
NM_001258271.2:c.1682A>G
NM_001258273.2:c.959A>G
NM_001258274.3:c.959A>G
NM_001354615.2:c.959A>G
NM_001354616.2:c.959A>G
NM_001354617.2:c.959A>G
NM_001354618.2:c.959A>G
NM_001354619.2:c.959A>G
NM_001354620.2:c.1388A>G
NM_001354621.2:c.659A>G
NM_001354622.2:c.659A>G
NM_001354623.2:c.659A>G
NM_001354624.2:c.608A>G
NM_001354625.2:c.608A>G
NM_001354626.2:c.608A>G
NM_001354627.2:c.608A>G
NM_001354628.2:c.1682A>G
NM_001354629.2:c.1583A>G
NM_001354630.2:c.1682A>G
NP_000240.1:p.Tyr561Cys
NP_000240.1:p.Tyr561Cys
NP_001161089.1:p.Tyr463Cys
NP_001161090.1:p.Tyr320Cys
NP_001161091.1:p.Tyr320Cys
NP_001245200.1:p.Tyr561Cys
NP_001245202.1:p.Tyr320Cys
NP_001245203.1:p.Tyr320Cys
NP_001341544.1:p.Tyr320Cys
NP_001341545.1:p.Tyr320Cys
NP_001341546.1:p.Tyr320Cys
NP_001341547.1:p.Tyr320Cys
NP_001341548.1:p.Tyr320Cys
NP_001341549.1:p.Tyr463Cys
NP_001341550.1:p.Tyr220Cys
NP_001341551.1:p.Tyr220Cys
NP_001341552.1:p.Tyr220Cys
NP_001341553.1:p.Tyr203Cys
NP_001341554.1:p.Tyr203Cys
NP_001341555.1:p.Tyr203Cys
NP_001341556.1:p.Tyr203Cys
NP_001341557.1:p.Tyr561Cys
NP_001341558.1:p.Tyr528Cys
NP_001341559.1:p.Tyr561Cys
LRG_216t1:c.1682A>G
LRG_216:g.53933A>G
LRG_216p1:p.Tyr561Cys
NC_000003.11:g.37083773A>G
NM_000249.3:c.1682A>G

Protein change:

Y203C

Links:

dbSNP: rs1289807424

NCBI 1000 Genomes Browser:

rs1289807424

Molecular consequence:

NM_000249.4:c.1682A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1388A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1682A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.959A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1388A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.659A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.659A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.659A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1682A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1583A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1682A>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
SCV000669524	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (May 23, 2023)	germline	clinical testing	Citation Link,
SCV000909037	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 26, 2023)	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

SCV000669524

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(May 23, 2023)

germline

clinical testing

Citation Link,

SCV000909037

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 26, 2023)

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	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

Details of each submission

From Ambry Genetics, SCV000669524.5

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

Description

The p.Y561C variant (also known as c.1682A>G), located in coding exon 15 of the MLH1 gene, results from an A to G substitution at nucleotide position 1682. The tyrosine at codon 561 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available 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

From Color Diagnostics, LLC DBA Color Health, SCV000909037.3

#	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 tyrosine with cysteine at codon 561 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31396 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

Last Updated: Apr 20, 2024

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