MSH6 p.Tyr214Tyr

Variant names:

• chr2-47798625-C-T
• rs1800937
• NM_000179.3:c.642C>T
• MSH6 p.Tyr214Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -21 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Very_StrongBP7

The NM_000179.3(MSH6):c.642C>T (p.Tyr214Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0912 (AC=146,849) in the gnomAD database across 1,610,204 control chromosomes, including 7,851 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.107. In-silico predictor (AlphaMissense) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.072 (550 hom., cov: 32)
  • Exomes 𝑓: 0.093 (7301 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:25
• Conservation: PhyloP100: -2.00
• Publications: 39 publications found

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

MSH6 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -21 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (25/25 total B/LB).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1067 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH6 NM_000179.3	MANE Select	c.642C>T p.Tyr214Tyr	synonymous	Exon 4 of 10	Prot: NP_000170.1 UniProt:
	MSH6 NM_001281493.2		c.-265C>T	5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	Prot: NP_001268422.1 UniProt:
	MSH6 NM_001281494.2		c.-265C>T	5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	Prot: NP_001268423.1 UniProt:

MSH6 NM_000179.3

MANE Select

HGVSc / HGVSpc.642C>Tp.Tyr214Tyr

Exon rankExon 4 of 10

synonymous

Prot: NP_000170.1UniProt: P52701-1

MSH6 NM_001281493.2

HGVSc / HGVSpc.-265C>T

Exon rankExon 3 of 9

5_prime_UTR_premature_start_codon_gain

Prot: NP_001268422.1UniProt: P52701-4

MSH6 NM_001281494.2

HGVSc / HGVSpc.-265C>T

Exon rankExon 4 of 10

5_prime_UTR_premature_start_codon_gain

Prot: NP_001268423.1UniProt: P52701-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH6 ENST00000234420.11	TSL:1MANE Select	c.642C>T p.Tyr214Tyr	synonymous	Exon 4 of 10	Prot: ENSP00000234420.5 UniProt:
	MSH6 ENST00000445503.5	TSL:1	n.472C>T	non_coding_transcript_exon	Exon 3 of 9	Prot: ENSP00000405294.1 UniProt:
	MSH6 ENST00000936511.1		c.642C>T p.Tyr214Tyr	synonymous	Exon 4 of 10	Prot: ENSP00000606570.1 UniProt:

MSH6 ENST00000234420.11

TSL:1MANE Select

HGVSc / HGVSpc.642C>Tp.Tyr214Tyr

Exon rankExon 4 of 10

synonymous

Prot: ENSP00000234420.5UniProt: P52701-1

MSH6 ENST00000445503.5

TSL:1

HGVSc / HGVSpn.472C>T

Exon rankExon 3 of 9

non_coding_transcript_exon

Prot: ENSP00000405294.1UniProt: F8WAX8

MSH6 ENST00000936511.1

HGVSc / HGVSpc.642C>Tp.Tyr214Tyr

Exon rankExon 4 of 10

synonymous

Prot: ENSP00000606570.1UniProt: A0ACI8TYH3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0719	AC:10921	Hom:550	AN:151930	Cov:32
GnomAD2 exomes	AF: 0.0711	AC:17523	Hom:	AN:246622	Cov:
GnomAD4 exome	AF: 0.0932	AC:135926	Hom:7301	AN:1458156	Cov:34
GnomAD4 genome	AF: 0.0718	AC:10923	Hom:550	AN:152048	Cov:32
TOPMed (Bravo)	AF: 0.0614	AC:16263	Hom:721	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0794	AC:14375	Hom:760	AN:180950	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0615	AC:144	Hom:2	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000542	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0867	AC:26	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0691	AC:899	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00924	AC:32	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0103	AC:20	Hom:	AN:1946	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.000114	AC:14	Hom:0	AN:122624	Cov:
Turkish Variome	AF: 0.0325	AC:216	Hom:1	AN:6650	Cov:
UK10K	AF: 0.104	AC:787	Hom:	AN:7562	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.114 *	1268	11104	0.124 *	2183	17616
BipEx(Bipolar disorder (including schizoaffective))	0.114	3244	28420	0.113	3265	28844
Epi25(Epilepsy)	0.0845	3546	41958	0.0852	5701	66888
SCHEMA(Schizophrenia)	0.0710	8895	125210	0.0830	16643	200434

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Lynch syndrome 5 (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	1	Carcinoma of colon (1)
-	-	1	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.036
AlphaMissense	Benign	0.25
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.23
DANN	Benign	0.92
GPN-Star LLR	N/A	1.6
GPN-Star score	N/A	1.6
Mutation Taster	N/A	299/1	polymorphism (auto)
PhyloP100	Benign	-2.0
RBP_binding_hub_radar	N/A	1.1
RBP_regulation_power_radar	N/A	2.2

Showing 11 of 11 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1800937;

hg19: chr2-48025764;

COSMIC: COSV52279626;

COSMIC: COSV52279626;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar