Submissions for variant NM_007294.4(BRCA1):c.512dup (p.Gln172fs)

dbSNP: rs587781487

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241064	SCV000299469	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000129450	SCV000184220	pathogenic	Hereditary cancer-predisposing syndrome	2018-02-13	criteria provided, single submitter	clinical testing	The c.512dupT pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a duplication of T at nucleotide position 512, causing a translational frameshift with a predicted alternate stop codon (p.Q172Tfs*10). This alteration, designated also as p.Gln172ThrfsTer10, was reported in an Indian patient with ovarian cancer who also had a family history of breast cancer (Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000168444	SCV000219141	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln172Thrfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 141091). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26911350).
GeneDx	RCV000236963	SCV000293092	pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA1 is denoted c.512dupT at the cDNA level and p.Gln172ThrfsX10 (Q172TfsX10) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CGGA[dupT]ACAA. The duplication causes a frameshift, which changes a Glutamine to a Threonine at codon 172, and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCAc.512dupT has been reported in association with breast and ovarian cancer (Mannan 2016). We consider this variant to be pathogenic.
Bioinformatics dept., Datar Cancer Genetics Limited, India	RCV000241064	SCV000583608	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129450	SCV001340639	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.