rs35819209

Variant names:

• chr2-47783411-T-C
• rs35819209
• NM_000179.3:c.178T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47783411-T-C
• chr2-47783411-T-G
• chr2-47783411-T-A

Variant summary

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

The NM_001406799.1(MSH6):​c.-151T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000642 in 1,526,992 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 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: MSH6 NM_001406799.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.61
• Publications: 4 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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=-0.86).
• BP6: Variant 2-47783411-T-C is Benign according to our data. Variant chr2-47783411-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406799.1. 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.178T>C	p.Leu60Leu	synonymous	Exon 1 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406799.1		c.-151T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001393728.1
	MSH6	NM_001406807.1		c.-751T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001393736.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.178T>C	p.Leu60Leu	synonymous	Exon 1 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.178T>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.178T>C	p.Leu60Leu	synonymous	Exon 1 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151948 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000851 AC: 11 AN: 129296 AF XY: 0.0000966

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000164

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000647 AC: 89 AN: 1375044 Hom.: 0 Cov.: 32 AF XY: 0.0000811 AC XY: 55 AN XY: 678216

African (AFR) AF: 0.00 AC: 0 AN: 28918

American (AMR) AF: 0.00 AC: 0 AN: 29748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23314

East Asian (EAS) AF: 0.00 AC: 0 AN: 34586

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.0000802 AC: 86 AN: 1071778

Other (OTH) AF: 0.0000354 AC: 2 AN: 56544

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151948 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74222

African (AFR) AF: 0.0000242 AC: 1 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000832 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Lynch syndrome 5 (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.2
DANN	Benign	0.67
PhyloP100		-1.6
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs35819209; hg19: chr2-48010550;