ENST00000652107.1:c.-38+17927G>A

Variant names:

• chr2-47755433-G-A
• rs441327
• ENST00000652107.1:c.-38+17927G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000652107.1(MSH6):​c.-38+17927G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 151,826 control chromosomes in the GnomAD database, including 14,725 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14725 hom., cov: 30)
• Consequence: MSH6 ENST00000652107.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 5 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: G2P, ClinGen, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• 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, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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

LOC105374589 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105374589	XR_940070.3	n.-46G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000652107.1	c.-38+17927G>A		intron_variant	Intron 3 of 11			ENSP00000498629.1
MSH6	ENST00000454137.5	n.621-2256G>A		intron_variant	Intron 3 of 3	3
ENSG00000304164	ENST00000800214.1	n.*1C>T		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65429 AN: 151710 Hom.: 14689 Cov.: 30

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.420

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.431 AC: 65511 AN: 151826 Hom.: 14725 Cov.: 30 AF XY: 0.440 AC XY: 32621 AN XY: 74208

African (AFR) AF: 0.457 AC: 18895 AN: 41380

American (AMR) AF: 0.513 AC: 7801 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1315 AN: 3468

East Asian (EAS) AF: 0.694 AC: 3583 AN: 5164

South Asian (SAS) AF: 0.631 AC: 3042 AN: 4818

European-Finnish (FIN) AF: 0.425 AC: 4488 AN: 10552

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 24988 AN: 67932

Other (OTH) AF: 0.426 AC: 891 AN: 2090

Alfa AF: 0.392 Hom.: 19954

Bravo AF: 0.441

Asia WGS AF: 0.634 AC: 2202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.71
PhyloP100		1.1

Splicing

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

Other links and lift over

dbSNP: rs441327; hg19: chr2-47982572;