VCV000428303.18 - ClinVar

NM_000179.3(MSH6):c.3664T>G (p.Phe1222Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000179.3(MSH6):c.3664T>G (p.Phe1222Val)

Variation ID: 428303 Accession: VCV000428303.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47806221 (GRCh38) [ NCBI UCSC ] 2: 48033360 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 25, 2017	May 1, 2024	Aug 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.3664T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Phe1222Val	missense
NM_001281492.2:c.3274T>G	NP_001268421.1:p.Phe1092Val	missense
NM_001281493.2:c.2758T>G	NP_001268422.1:p.Phe920Val	missense
NM_001281494.2:c.2758T>G	NP_001268423.1:p.Phe920Val	missense
NC_000002.12:g.47806221T>G
NC_000002.11:g.48033360T>G
NG_007111.1:g.28075T>G
NG_008397.1:g.104455A>C
LRG_219:g.28075T>G
LRG_219t1:c.3664T>G	LRG_219p1:p.Phe1222Val

... more HGVS ... less HGVS

Protein change

F1222V, F1092V, F920V

Other names

Canonical SPDI

NC_000002.12:47806220:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA071813 dbSNP: rs775265464 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MSH6		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	9159	9475

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 19, 2021	RCV000491642.6
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2023	RCV001370230.6
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV002268131.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000908428.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552357.4 First in ClinVar: Jul 28, 2022 Last updated: Aug 18, 2023
Uncertain significance (Aug 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001566697.4 First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024	Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1222 of the MSH6 protein (p.Phe1222Val). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1222 of the MSH6 protein (p.Phe1222Val). This variant is present in population databases (rs775265464, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Oct 19, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000580126.6 First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 30680046‚ 33471991 Comment: The p.F1222V variant (also known as c.3664T>G), located in coding exon 8 of the MSH6 gene, results from a T to G substitution at nucleotide … (more) The p.F1222V variant (also known as c.3664T>G), located in coding exon 8 of the MSH6 gene, results from a T to G substitution at nucleotide position 3664. The phenylalanine at codon 1222 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in conjunction with an APC mutation in a patient diagnosed with colon cancer at age 68 (Henn J et al. Hered Cancer Clin Pract. 2019 Jan;17:5). This variant was reported in 0/60,466 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 through reptiles. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1222 of the MSH6 protein (p.Phe1222Val). This variant is present in population databases (rs775265464, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.F1222V variant (also known as c.3664T>G), located in coding exon 8 of the MSH6 gene, results from a T to G substitution at nucleotide position 3664. The phenylalanine at codon 1222 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in conjunction with an APC mutation in a patient diagnosed with colon cancer at age 68 (Henn J et al. Hered Cancer Clin Pract. 2019 Jan;17:5). This variant was reported in 0/60,466 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 through reptiles. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes.	Henn J	Hereditary cancer in clinical practice	2019	PMID: 30680046

Text-mined citations for rs775265464 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.3664T>G (p.Phe1222Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs775265464 ...