rs3045983

Variant names:

• chr5-80654922-GCCCCCAGCT-G
• rs3045983
• NM_002439.5:c.199_207delCCAGCTCCC

Your query was ambiguous. Multiple possible variants found:

• chr5-80654922-GCCCCCAGCT-G
• chr5-80654922-GCCCCCAGCT-GCCCCCAGCTCCCCCAGCT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_002439.5(MSH3):​c.199_207delCCAGCTCCC​(p.Pro67_Pro69del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,521,560 control chromosomes in the GnomAD database, including 63,065 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P67P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5185 hom., cov: 0)
  • Exomes 𝑓: 0.27 (57880 hom.)
• Consequence: MSH3 NM_002439.5 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0640
• Publications: 10 publications found

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

DHFR Gene-Disease associations (from GenCC):

• constitutional megaloblastic anemia with severe neurologic disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002439.5.
• BP6: Variant 5-80654922-GCCCCCAGCT-G is Benign according to our data. Variant chr5-80654922-GCCCCCAGCT-G is described in ClinVar as Benign. ClinVar VariationId is 402590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	Exon 1 of 24	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-442_-434delAGCTGGGGG		5_prime_UTR_variant	Exon 1 of 6	ENST00000439211.7	NP_000782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	Exon 1 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000667069.1	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	Exon 1 of 22			ENSP00000499502.1
MSH3	ENST00000670357.1	n.199_207delCCAGCTCCC		non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000499791.1
DHFR	ENST00000439211.7	c.-442_-434delAGCTGGGGG		5_prime_UTR_variant	Exon 1 of 6	1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000658259.1	c.-271_-263delCCCCCAGCT		upstream_gene_variant				ENSP00000499617.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 38926 AN: 150902 Hom.: 5181 Cov.: 0

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0474

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.309 AC: 39028 AN: 126454 AF XY: 0.318

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.0633

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.272 AC: 373255 AN: 1370550 Hom.: 57880 AF XY: 0.276 AC XY: 187394 AN XY: 678858

African (AFR) AF: 0.321 AC: 9270 AN: 28874

American (AMR) AF: 0.232 AC: 6906 AN: 29744

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7046 AN: 23576

East Asian (EAS) AF: 0.0379 AC: 1254 AN: 33128

South Asian (SAS) AF: 0.353 AC: 27589 AN: 78140

European-Finnish (FIN) AF: 0.219 AC: 10510 AN: 47928

Middle Eastern (MID) AF: 0.442 AC: 2412 AN: 5458

European-Non Finnish (NFE) AF: 0.274 AC: 292257 AN: 1066972

Other (OTH) AF: 0.282 AC: 16011 AN: 56730

GnomAD4 genome AF: 0.258 AC: 38939 AN: 151010 Hom.: 5185 Cov.: 0 AF XY: 0.256 AC XY: 18875 AN XY: 73796

African (AFR) AF: 0.281 AC: 11504 AN: 40896

American (AMR) AF: 0.231 AC: 3512 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3468

East Asian (EAS) AF: 0.0474 AC: 240 AN: 5064

South Asian (SAS) AF: 0.317 AC: 1522 AN: 4798

European-Finnish (FIN) AF: 0.204 AC: 2142 AN: 10502

Middle Eastern (MID) AF: 0.331 AC: 96 AN: 290

European-Non Finnish (NFE) AF: 0.267 AC: 18066 AN: 67748

Other (OTH) AF: 0.285 AC: 600 AN: 2104

Alfa AF: 0.138 Hom.: 557

Asia WGS AF: 0.210 AC: 730 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25927356) -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Hereditary cancer-predisposing syndrome Benign:1

Apr 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 Benign:1

Jan 10, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064
Mutation Taster		=174/126	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3045983; hg19: chr5-79950741; COSMIC: COSV54151158; COSMIC: COSV54151158;