chr2-47783515-C-G

Variant names:

• chr2-47783515-C-G
• rs55927047
• NM_000179.3:c.260+22C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001406795.1(MSH6):​c.260+22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,391,608 control chromosomes in the GnomAD database, including 21,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1551 hom., cov: 30)
  • Exomes 𝑓: 0.17 (20096 hom.)
• Consequence: MSH6 NM_001406795.1 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: -2.21
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-47783515-C-G is Benign according to our data. Variant chr2-47783515-C-G is described in ClinVar as Benign. ClinVar VariationId is 89295.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406795.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.260+22C>G		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.260+22C>G		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.260+22C>G		intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.260+22C>G		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.260+22C>G		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000936511.1		c.260+22C>G		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19187 AN: 148068 Hom.: 1553 Cov.: 30

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.0614

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.139 AC: 4248 AN: 30570 AF XY: 0.142

Gnomad AFR exome AF: 0.0588

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.175 AC: 217153 AN: 1243430 Hom.: 20096 Cov.: 33 AF XY: 0.173 AC XY: 103601 AN XY: 600298

African (AFR) AF: 0.0432 AC: 1039 AN: 24050

American (AMR) AF: 0.113 AC: 1672 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 2816 AN: 17300

East Asian (EAS) AF: 0.000378 AC: 11 AN: 29078

South Asian (SAS) AF: 0.0785 AC: 4394 AN: 55980

European-Finnish (FIN) AF: 0.122 AC: 5085 AN: 41792

Middle Eastern (MID) AF: 0.170 AC: 683 AN: 4024

European-Non Finnish (NFE) AF: 0.192 AC: 193416 AN: 1005430

Other (OTH) AF: 0.158 AC: 8037 AN: 51020

GnomAD4 genome AF: 0.129 AC: 19185 AN: 148178 Hom.: 1551 Cov.: 30 AF XY: 0.126 AC XY: 9088 AN XY: 72358

African (AFR) AF: 0.0552 AC: 2216 AN: 40134

American (AMR) AF: 0.126 AC: 1884 AN: 15006

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 537 AN: 3430

East Asian (EAS) AF: 0.00104 AC: 5 AN: 4822

South Asian (SAS) AF: 0.0614 AC: 283 AN: 4610

European-Finnish (FIN) AF: 0.124 AC: 1279 AN: 10304

Middle Eastern (MID) AF: 0.176 AC: 45 AN: 256

European-Non Finnish (NFE) AF: 0.187 AC: 12491 AN: 66720

Other (OTH) AF: 0.148 AC: 302 AN: 2042

Alfa AF: 0.140 Hom.: 227

Bravo AF: 0.127

Asia WGS AF: 0.0410 AC: 146 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	2	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Lynch syndrome (1)
-	-	1	Lynch syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.6
DANN	Benign	0.74
PhyloP100		-2.2
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55927047; hg19: chr2-48010654; COSMIC: COSV52278035; COSMIC: COSV52278035;