NM_017654.4(SAMD9):c.2026A>G (p.Lys676Glu) AND Monosomy 7 myelodysplasia and leukemia syndrome 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 10, 2020
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001270306.1

Allele description [Variation Report for NM_017654.4(SAMD9):c.2026A>G (p.Lys676Glu)]

NM_017654.4(SAMD9):c.2026A>G (p.Lys676Glu)

Gene:

SAMD9:sterile alpha motif domain containing 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.2

Genomic location:

Preferred name:

NM_017654.4(SAMD9):c.2026A>G (p.Lys676Glu)

HGVS:

NC_000007.14:g.93104072T>C
NG_023419.1:g.18952A>G
NM_001193307.2:c.2026A>G
NM_017654.4:c.2026A>GMANE SELECT
NP_001180236.1:p.Lys676Glu
NP_060124.2:p.Lys676Glu
NC_000007.13:g.92733385T>C

Protein change:

K676E; LYS676GLU

Links:

OMIM: 610456.0007; dbSNP: rs1791586314

NCBI 1000 Genomes Browser:

rs1791586314

Molecular consequence:

NM_001193307.2:c.2026A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_017654.4:c.2026A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Monosomy 7 myelodysplasia and leukemia syndrome 2
Identifiers:: MONDO: MONDO:0030801; MedGen: C5436668; OMIM: 619041

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001450514	OMIM	no assertion criteria provided	Pathogenic (Dec 10, 2020)	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 30046003, 2569483

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001450514

OMIM

no assertion criteria provided

Pathogenic
(Dec 10, 2020)

unknown

literature only

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.

Wong JC, Bryant V, Lamprecht T, Ma J, Walsh M, Schwartz J, Del Pilar Alzamora M, Mullighan CG, Loh ML, Ribeiro R, Downing JR, Carroll WL, Davis J, Gold S, Rogers PC, Israels S, Yanofsky R, Shannon K, Klco JM.

JCI Insight. 2018 Jul 26;3(14). doi:pii: 121086. 10.1172/jci.insight.121086.

PubMed [citation]

PMID:: 30046003
PMCID:: PMC6124395

Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7.

Shannon KM, Turhan AG, Chang SS, Bowcock AM, Rogers PC, Carroll WL, Cowan MJ, Glader BE, Eaves CJ, Eaves AC, et al.

J Clin Invest. 1989 Sep;84(3):984-9.

PubMed [citation]

PMID:: 2569483
PMCID:: PMC329745

Details of each submission

From OMIM, SCV001450514.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 brothers (family 2) with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; 619041), Wong et al. (2018) identified a germline heterozygous c.2026A-G transition (c.2026A-G, NM_017654) in exon 3 of the SAMD9 gene, resulting in a lys676-to-glu (K676E) substitution. The mutation, which was not present in either parent, was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. HEK293T cells transfected with the mutation showed suppressed cell cycle progression with almost no proliferation compared to controls, consistent with a gain-of-function effect. One patient had AML and the other had MDS; both had loss of the paternal chromosome 7 in bone marrow cells. The molecular findings supported the hypothesis that the somatic loss of chromosome 7 results from selective pressure to favor the growth of hematopoietic stem cells that carry the SAMD9 mutation, suggesting 'adaptation by aneuploidy' as a pathogenic mechanism. The family had previously been reported by Shannon et al. (1989).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 23, 2022

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