2-47783509-T-G

Variant names:

• chr2-47783509-T-G
• rs1450747755
• NM_000179.3:c.260+16T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000179.3(MSH6):​c.260+16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 1,217,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.601
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-47783509-T-G is Benign according to our data. Variant chr2-47783509-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 491902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.260+16T>G		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.260+16T>G		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.260+16T>G		intron	N/A	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.260+16T>G		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.260+16T>G		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000700002.1		c.260+16T>G		intron	N/A	ENSP00000514750.1

Frequencies

GnomAD3 genomes AF: 0.0000236 AC: 3 AN: 127214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000347

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 45 AN: 1217076 Hom.: 0 Cov.: 34 AF XY: 0.0000443 AC XY: 26 AN XY: 586776

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24048

American (AMR) AF: 0.000139 AC: 2 AN: 14366

Ashkenazi Jewish (ASJ) AF: 0.000122 AC: 2 AN: 16404

East Asian (EAS) AF: 0.00 AC: 0 AN: 29114

South Asian (SAS) AF: 0.000178 AC: 9 AN: 50510

European-Finnish (FIN) AF: 0.000101 AC: 4 AN: 39506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.0000243 AC: 24 AN: 989496

Other (OTH) AF: 0.0000808 AC: 4 AN: 49522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000236 AC: 3 AN: 127302 Hom.: 0 Cov.: 31 AF XY: 0.0000160 AC XY: 1 AN XY: 62522

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000296 AC: 1 AN: 33734

American (AMR) AF: 0.00 AC: 0 AN: 13524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3058

East Asian (EAS) AF: 0.00 AC: 0 AN: 4292

South Asian (SAS) AF: 0.00 AC: 0 AN: 3832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0000348 AC: 2 AN: 57544

Other (OTH) AF: 0.00 AC: 0 AN: 1758

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00295 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Benign:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Jul 29, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		-0.60
PromoterAI		-0.029	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1450747755; hg19: chr2-48010648;