Submissions for variant NM_000057.4(BLM):c.191A>T (p.Asp64Val)

gnomAD frequency: 0.00026  dbSNP: rs140382474

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656775	SCV000149194	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with a personal history of breast, colorectal, or other cancers (Tsaousis et al., 2019; Rizzolo et al., 2019; Sandoval et al., 2021; DeRycke et al., 2017; Zhang et al., 2015); This variant is associated with the following publications: (PMID: 26580448, 30613976, 28944238, 31937788, 33606809, 31159747)
Eurofins Ntd Llc (ga)	RCV000656775	SCV000228762	uncertain significance	not provided	2015-04-24	criteria provided, single submitter	clinical testing
Invitae	RCV000460513	SCV000543353	benign	Bloom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000460513	SCV000611375	uncertain significance	Bloom syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574815	SCV000672903	likely benign	Hereditary cancer-predisposing syndrome	2018-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneKor MSA	RCV000574815	SCV000821900	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000460513	SCV001652747	uncertain significance	Bloom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656775	SCV002010767	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000460513	SCV002012383	uncertain significance	Bloom syndrome	2021-09-09	criteria provided, single submitter	clinical testing	The BLM c.191A>T (p.Asp64Val) missense change has a maximum subpopulation frequency of 0.054% in gnomAD v2.1.1, including one homozygous occurrence (https://gnomad.broadinstitute.org/variant/15-91292689-A-T). It has also been identified in 2/1358 non-cancer control individuals in a study of individuals with multiple primary cancers (PMID: 29641532). Data submitted to ClinVar indicate that this variant has been seen in trans with a pathogenic variant or in the homozygous state in an individual without severe disease (ClinVar Accession: SCV000672903.3). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria applied.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656775	SCV002046949	likely benign	not provided	2023-07-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574815	SCV002533669	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800401	SCV002548366	uncertain significance	not specified	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: BLM c.191A>T (p.Asp64Val) results in a non-conservative amino acid change located in the Bloom syndrome protein, N-terminal domain (IPR032437) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 250804 control chromosomes, predominantly at a frequency of 0.0005 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.00024 vs 0.0035), allowing no conclusion about variant significance. c.191A>T has been reported in the literature in individuals affected with autosomal dominant cancer-predisposition syndromes, breast and/or ovarian cancer (Zhang_2015, Rizzolo_2019, Tsaousis_2019, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000460513	SCV001456976	benign	Bloom syndrome	2019-08-06	no assertion criteria provided	clinical testing