NM_000057.4(BLM):c.2983T>C (p.Tyr995His) AND Bloom syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 30, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000628665.8

Allele description [Variation Report for NM_000057.4(BLM):c.2983T>C (p.Tyr995His)]

NM_000057.4(BLM):c.2983T>C (p.Tyr995His)

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.2983T>C (p.Tyr995His)

HGVS:

NC_000015.10:g.90790808T>C
NG_007272.1:g.78437T>C
NM_000057.4:c.2983T>CMANE SELECT
NM_001287246.2:c.2983T>C
NM_001287247.2:c.2983T>C
NM_001287248.2:c.1858T>C
NP_000048.1:p.Tyr995His
NP_001274175.1:p.Tyr995His
NP_001274176.1:p.Tyr995His
NP_001274177.1:p.Tyr620His
LRG_20:g.78437T>C
NC_000015.9:g.91334038T>C
NM_000057.2:c.2983T>C
NM_000057.3:c.2983T>C

Protein change:

Y620H

Links:

dbSNP: rs142723411

NCBI 1000 Genomes Browser:

rs142723411

Molecular consequence:

NM_000057.4:c.2983T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287246.2:c.2983T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287247.2:c.2983T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001287248.2:c.1858T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Bloom syndrome (BLM)
Synonyms:: Bloom-Torre-Machacek syndrome; Growth deficiency, sun-sensitive, telangiectatic, hypo and hyperpigmented skin, predisposition to malignancy and chromosomal instability
Identifiers:: MONDO: MONDO:0008876; MedGen: C0005859; Orphanet: 125; OMIM: 210900

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Human beta-D-galactosidase mRNA, complete cds
Human beta-D-galactosidase mRNA, complete cds
gi|179400|gb|M27507.1|HUMBDGALA

Nucleotide
Galnt3 [Arvicanthis niloticus]
Galnt3 [Arvicanthis niloticus]
Gene ID:117703066

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000749570	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23129629, 28492532
SCV002090497	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jul 24, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000749570

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 30, 2023)

germline

clinical testing

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

SCV002090497

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jul 24, 2020)

germline

clinical testing

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

Citations

PubMed

Non-Bloom syndrome-associated partial and total loss-of-function variants of BLM helicase.

Mirzaei H, Schmidt KH.

Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19357-62. doi: 10.1073/pnas.1210304109. Epub 2012 Nov 5.

PubMed [citation]

PMID:: 23129629
PMCID:: PMC3511070

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000749570.5

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 995 of the BLM protein (p.Tyr995His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 524798). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 23129629). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From Natera, Inc., SCV002090497.1

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

#	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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