rs3136228

Variant names:

• chr2-47782677-T-G
• rs3136228
• ENST00000652107.1:c.-37-8250T>G

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 -20 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Very_Strong

The ENST00000652107.1(MSH6):c.-37-8250T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000652107.1 is not a MANE Select or MANE Plus Clinical transcript for MSH6; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.291 (AC=44,339) in the gnomAD database across 152,188 control chromosomes, including 7,066 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.361. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

• Frequency: Genomes: 𝑓 0.29 (7066 hom., cov: 33)
• Consequence: MSH6 ENST00000652107.1 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.0530
• Publications: 21 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

ENSG00000304164 (HGNC:):

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 -20 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); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3608 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000652107.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000652107.1		c.-37-8250T>G		intron	N/A	ENSP00000498629.1	A0A494C0M1
	ENSG00000304164	ENST00000800214.1		n.20A>C		non_coding_transcript_exon	Exon 1 of 2

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.291	AC:44313	Hom:7057	AN:152070	Cov:33
GnomAD4 genome	AF: 0.291	AC:44339	Hom:7066	AN:152188	Cov:33
TOPMed (Bravo)	AF: 0.284	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.336	AC:192543	Hom:33817	AN:573894	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.325	AC:760	Hom:129	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.00359	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.310	AC:93	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.0910	AC:319	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.216	AC:38	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.000285	AC:35	Hom:6	AN:122668	Cov:
Turkish Variome	AF: 0.290	AC:448	Hom:70	AN:1546	Cov:
UK10K	AF: 0.371	AC:2802	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00234	AC:21	Hom:0	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.0
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.44
GPN-Star LLR	N/A	4.2
GPN-Star score	N/A	-0.39
PhyloP100	Benign	0.053
PromoterAI	N/A	0.019	Neutral

Showing 8 of 8 scores

Splicing Scores

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

Showing 1 of 1 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.

Other links and lift over

dbSNP: rs3136228;

hg19: chr2-48009816;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar