rs864622041

chr2-47805693-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000179.3(MSH6):c.3632T>C(p.Leu1211Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1211F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.51

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000179.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47805692-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1470503.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-47805693-T-C is Pathogenic according to our data. Variant chr2-47805693-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 219294.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47805693-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3632T>C	p.Leu1211Pro	missense_variant	7/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3632T>C	p.Leu1211Pro	missense_variant	7/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458930 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 21, 2019	Multifactorial likelihood analysis posterior probability >0.99 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 02, 2023	The p.Leu1211Pro variant in MSH6 has been reported in at least 3 individuals with Lynch syndrome and segregated with disease in 2 affected relatives from 1 family (Rossi 2017 PMID: 28874130, de Paula 2021 PMID: 33647816, Libera 2016, Doctoral Thesis, Ambry pers. comm., Invitae pers. comm.). In addition, tumors sampled from 2 of these individuals showed either high microsatellite instability or lacked MSH6 expression. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as Pathogenic on June 21, 2019 by the ClinGen-approved International Society for Gastrointestinal Hereditary Tumors (InSiGHT) expert panel (ClinVar Variation ID 219294). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS3, PS4_Supporting, PM2_Supporting, PP3. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2020	This missense variant replaces leucine with proline at codon 1211 of the MSH6 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). An in vitro DNA mismatch repair assay found this variant protein to have nearly no activity compared to wildtype (PMID: 31965077). This variant has been observed in at least three individuals and a family affected with Lynch syndrome and/or Lynch syndrome-associated cancer with tumor histopathology consistent with DNA mismatch repair deficiency (PMID: 21520333, 28471861, 28874130; Leiden Open Variation Database Individual #00188773). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 2021	The p.L1211P pathogenic mutation (also known as c.3632T>C), located in coding exon 7 of the MSH6 gene, results from a T to C substitution at nucleotide position 3632. The leucine at codon 1211 is replaced by proline, an amino acid with similar properties. This alteration was reported in a Brazilian family suspected of having Lynch syndrome (Rossi BM et al. BMC Cancer. 2017 Sep;17:623). This alteration was also reported in a proband whose endometrial and colorectal tumors demonstrated isolated of MSH6 staining on immunohistochemistry (IHC) and family history met Amsterdam II criteria for Lynch syndrome (Fokkema IF et al. Hum Mutat, 2011 May;32:557-63). In our internal cohort, this alteration has also been identified in an individual whose endometrial tumor demonstrated isolated loss of MSH6 staining on IHC and in individuals whose family histories met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data). This variant also demonstrated deficient mismatch repair activity in an in vitro complementation assay (Drost M et al. Genet Med, 2020 05;22:847-856). Based on internal structural assessment, this alteration destabilizes the fold of the ATPase domain (Warren JJ et al. Mol Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 24, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 06, 2023

The MSH6 c.3632T>C (p.Leu1211Pro) variant has been reported in the published literature in an affected family with Lynch Syndrome (PMID: 28874130 (2017)). An in vitro mismatch repair study demonstrated that this variant had no activity as compared to the wild type (PMID: 31965077 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1211 of the MSH6 protein (p.Leu1211Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical feature of Lynch syndrome (PMID: 28874130; Invitae). ClinVar contains an entry for this variant (Variation ID: 219294). 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) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.99
MutPred		0.94		.;.;.;Gain of disorder (P = 0.0483);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622041; hg19: chr2-48032832; COSMIC: COSV52277731; COSMIC: COSV52277731;