NM_000057.4(BLM):c.3970C>T (p.His1324Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000708669.6

Allele description [Variation Report for NM_000057.4(BLM):c.3970C>T (p.His1324Tyr)]

NM_000057.4(BLM):c.3970C>T (p.His1324Tyr)

Gene:

BLM:BLM RecQ like helicase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_000057.4(BLM):c.3970C>T (p.His1324Tyr)

HGVS:

NC_000015.10:g.90811300C>T
NG_007272.1:g.98929C>T
NM_000057.4:c.3970C>TMANE SELECT
NM_001287246.2:c.3970C>T
NM_001287247.2:c.3577C>T
NM_001287248.2:c.2845C>T
NP_000048.1:p.His1324Tyr
NP_001274175.1:p.His1324Tyr
NP_001274176.1:p.His1193Tyr
NP_001274177.1:p.His949Tyr
LRG_20t1:c.3970C>T
LRG_20:g.98929C>T
NC_000015.9:g.91354530C>T
NM_000057.2:c.3970C>T
NM_000057.3:c.3970C>T

Protein change:

H1193Y

Links:

dbSNP: rs748943489

NCBI 1000 Genomes Browser:

rs748943489

Molecular consequence:

NM_000057.4:c.3970C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287246.2:c.3970C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287247.2:c.3577C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287248.2:c.2845C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000821906	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001183184	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17407155, 23129629, 26247052, 31159747 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000821906

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 1, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001183184

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 1, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry.

German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA.

Hum Mutat. 2007 Aug;28(8):743-53.

PubMed [citation]

PMID:: 17407155

See all PubMed Citations (5)

Details of each submission

From GeneKor MSA, SCV000821906.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

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

From Ambry Genetics, SCV001183184.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.H1324Y variant (also known as c.3970C>T), located in coding exon 20 of the BLM gene, results from a C to T substitution at nucleotide position 3970. The histidine at codon 1324 is replaced by tyrosine, an amino acid with similar properties. This variant has been identified in one person with Bloom Syndrome and functional studies have shown that it preserves normal BLM protein function in reducing the levels of sister-chromatid exchanges in patient-derived cells (German J et al. Hum. Mutat., 2007 Aug;28:743-53; Perreault-Micale C et al. Mol Genet Genomic Med, 2015 Jul;3:363-73). Another study determined that this variant (reported as c.3970C>T, p.H1324T) was not sensitive to the DNA damaging agent, hydroxyurea, similar to wildtype (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62). This variant was also reported as a variant of unknown signifcance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Sep 29, 2024

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