rs1553408414

Variant names:

• chr2-47783467-A-G
• rs1553408414
• NM_000179.3:c.234A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-47783467-A-G
• chr2-47783467-A-C
• chr2-47783467-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_001406804.1(MSH6):​c.179A>G​(p.Asp60Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,299,424 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D60N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MSH6 NM_001406804.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0520
• 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: 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-47783467-A-G is Benign according to our data. Variant chr2-47783467-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455192.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406804.1. 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.234A>G	p.Arg78Arg	synonymous	Exon 1 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406804.1		c.179A>G	p.Asp60Gly	missense	Exon 1 of 10	NP_001393733.1
	MSH6	NM_001406795.1		c.234A>G	p.Arg78Arg	synonymous	Exon 1 of 11	NP_001393724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.234A>G	p.Arg78Arg	synonymous	Exon 1 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.234A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.234A>G	p.Arg78Arg	synonymous	Exon 1 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1299424 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 633018

African (AFR) AF: 0.00 AC: 0 AN: 25772

American (AMR) AF: 0.00 AC: 0 AN: 20116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 31450

South Asian (SAS) AF: 0.00 AC: 0 AN: 64722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5058

European-Non Finnish (NFE) AF: 0.00000193 AC: 2 AN: 1034476

Other (OTH) AF: 0.00 AC: 0 AN: 53576

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Uncertain	24
DANN	Benign	0.76
PhyloP100		0.052
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -1

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

Other links and lift over

dbSNP: rs1553408414; hg19: chr2-48010606;