2-47803479-G-C

Variant names:

• chr2-47803479-G-C
• rs587779932
• NM_000179.3:c.3232G>C
• MSH6 p.Val1078Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2_SupportingBP4_Moderate

The NM_000179.3(MSH6):c.3232G>C (p.Val1078Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000112 (AC=18) in the gnomAD database across 1,613,974 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000285. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V1078A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 134855); p.V1078I: Uncertain_significance (ClinVar VariationId 3693927, 1 star); p.V1078L: Uncertain_significance (ClinVar VariationId 1729213, 1 star); p.V1078= (synonymous): Benign (ClinVar VariationId 3903497, 1 star); p.V1078= (synonymous): Benign/Likely_benign (ClinVar VariationId 924451, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 2.34
• Publications: 1 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 7 pathogenic, 9 benign (OR vs. background: 3.9).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000285 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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.3232G>C p.Val1078Leu	missense	Exon 5 of 10	Prot: NP_000170.1 UniProt:
	MSH6 NM_001406795.1		c.3328G>C p.Val1110Leu	missense	Exon 6 of 11	Prot: NP_001393724.1
	MSH6 NM_001406813.1		c.3238G>C p.Val1080Leu	missense	Exon 5 of 10	Prot: NP_001393742.1

MSH6 NM_000179.3

MANE Select

HGVSc / HGVSpc.3232G>Cp.Val1078Leu

Exon rankExon 5 of 10

missense

Prot: NP_000170.1UniProt: P52701-1

MSH6 NM_001406795.1

HGVSc / HGVSpc.3328G>Cp.Val1110Leu

Exon rankExon 6 of 11

missense

Prot: NP_001393724.1

MSH6 NM_001406813.1

HGVSc / HGVSpc.3238G>Cp.Val1080Leu

Exon rankExon 5 of 10

missense

Prot: NP_001393742.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MSH6 ENST00000234420.11	TSL:1MANE Select	c.3232G>C p.Val1078Leu	missense	Exon 5 of 10	Prot: ENSP00000234420.5 UniProt:
	MSH6 ENST00000445503.5	TSL:1	n.*2579G>C	3_prime_UTR	Exon 4 of 9	Prot: ENSP00000405294.1 UniProt:
	MSH6 ENST00000445503.5	TSL:1	n.*2579G>C	non_coding_transcript_exon	Exon 4 of 9	Prot: ENSP00000405294.1 UniProt:

MSH6 ENST00000234420.11

TSL:1MANE Select

HGVSc / HGVSpc.3232G>Cp.Val1078Leu

Exon rankExon 5 of 10

missense

Prot: ENSP00000234420.5UniProt: P52701-1

MSH6 ENST00000445503.5

TSL:1

HGVSc / HGVSpn.*2579G>C

Exon rankExon 4 of 9

3_prime_UTR

Prot: ENSP00000405294.1UniProt: F8WAX8

MSH6 ENST00000445503.5

TSL:1

HGVSc / HGVSpn.*2579G>C

Exon rankExon 4 of 9

non_coding_transcript_exon

Prot: ENSP00000405294.1UniProt: F8WAX8

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: 0.0000329	AC:5	Hom:0	AN:152098	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251392	Cov:
GnomAD4 exome	AF: 0.00000889	AC:13	Hom:0	AN:1461876	Cov:33
GnomAD4 genome	AF: 0.0000329	AC:5	Hom:0	AN:152098	Cov:32
TOPMed (Bravo)	AF: 0.0000151	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000785	AC:3	Hom:0	AN:38222	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000748	5	66888
SCHEMA(Schizophrenia)	0.0000129	1	77570	0.0000144	2	139130

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Lynch syndrome 5 (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	1	-	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.89	D
FuncVEP CTI	Benign	0.035
GPN-Star LLR	N/A	-4.8
GPN-Star score	N/A	4.8
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.70	T
Mutation Taster	N/A	80/20	polymorphism
MutationAssessor	Benign	1.5	L
PhyloP100	Benign	2.3
popEVE	Benign	-2.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.73	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.2
REVEL	Benign	0.18
Sift	Benign	0.38	T
Sift4G	Benign	0.32	T
Varity_R	N/A	0.14
VESM-3B	Benign	-5.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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: rs587779932;

hg19: chr2-48030618;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar