Submissions for variant NM_007294.4(BRCA1):c.5074G>A (p.Asp1692Asn)

dbSNP: rs80187739

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217586	SCV000273244	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-21	criteria provided, single submitter	clinical testing	The c.5074G>A variant (also known as p.D1692N), located in coding exon 15 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5074. The amino acid change results in aspartic acid to asparagine at codon 1692, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Minigene RNA analysis shows that this variant results in the skipping of exon 17 and to use a cryptic splice donor site 153 base pairs of the 5' end of intron 17, the aberrant effect of which is also observed in a haploid cell survival assay (Ahlborn LB, et al. Breast Cancer Res.Treat. 2015;150(2):289-98; Findlay GM. Nature. 2018 10;562(7726):217-222). This alteration segregated with disease in a large family and is considered an Icelandic founder mutation (Bergthorsson JT, et al. Hum. Mutat. 1998 ; Suppl 1():S195-7). Functional and computational analyses of this variant at the protein level largely reflect the missense change to be tolerated (Abkevich V, et al. J. Med. Genet. 2004;41(7):492-507; Rowling PJ, et al. J. Biol. Chem. 2010;285(26):20080-7; Lee MS, et al. Cancer Res. 2010;70(12):4880-90; Vallon-Christersson J, et al. Hum. Mol. Genet. 2001;10(4):353-60; Bouwman P et al. Clin Cancer Res, 2020 Sep;26:4559-4568; Gaboriau DC et al. Biochem J, 2015 Mar;466:613-24). Of note, this alteration is also designated as 5193G>A in published literature. The nucleotide and amino acid positions are highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000255870	SCV000322096	pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and demonstrated to cause aberrant splicing, resulting predominantly in out-of-frame skipping of exon 17, as well as use of a cryptic splice donor site (Ahlborn et al., 2015); Described as an Icelandic founder variant which has been observed in individuals with breast or ovarian cancer (Arason et al., 1998; Bergthorsson et al., 1998; Janezic et al., 1999; Rafnar et al., 2004; Carter et al., 2018; Li et al., 2018; Zheng et al., 2018; Su et al., 2021); Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5193G>A; This variant is associated with the following publications: (PMID: 25722380, 30251169, 15235020, 25724305, 9452084, 20378548, 11157798, 20516115, 15571962, 15172985, 17305420, 23239986, 25748678, 24772314, 10196379, 27495310, 21447777, 16267036, 28726806, 29446198, 23199084, 21769658, 21147198, 12531920, 30078507, 30322717, 9500438, 29996917, 29884841, 32546644, 35665744, 32211327, 30130155, 9643283, 34917121, 36068545, 35171259, 25348405, 30209399)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031213	SCV000326135	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217586	SCV000904696	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1692 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional RNA studies have shown that this variant causes a splicing defect leading to skipping of exon 16 or in-frame retention of part of intron 15 (PMID: 25724305). This variant has been reported in individuals affected with familial breast/ovarian cancer (PMID: 9452084, 10196379, 11157798, 15571962). 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.
Invitae	RCV000496924	SCV001585898	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1692 of the BRCA1 protein (p.Asp1692Asn). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8460636, 9452084, 10196379, 15571962). It is commonly reported in individuals of Icelandic ancestry (PMID: 8460636, 9452084, 15571962). This variant is also known as 5193G>A. ClinVar contains an entry for this variant (Variation ID: 37632). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25748678, 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000031213	SCV002578917	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-20	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031213	SCV003843144	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2022-11-04	criteria provided, single submitter	clinical testing	The BRCA1 c.5074G>A (p.Asp1692Asn) missense change affects the last nucleotide of exon 16 and is predicted to abolish the native splice donor site. An in vitro study demonstrated that this variant leads to multiple aberrant transcripts, including one causing exon 17 skipping and another causing activation of a cryptic splice donor site that leads to an in-frame retention of 153 bp of intron 17 (PMID: 25724305). These published findings are also supported by internal data. This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 8460636, 9452084, 10196379, 15571962). It is commonly reported in individuals of Icelandic ancestry and genetic linkage analysis suggests that this is an Icelandic founder mutation (PMID: 8460636, 9452084, 15571962). It is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496924	SCV003923014	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5074G>A (p.Asp1692Asn) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251348 control chromosomes. c.5074G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. In families with this variant, 11 transmissions of the variant allele and 1 transmissions of the reference allele to affected individuals was reported. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in loss of function (Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=7, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031213	SCV000053813	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031213	SCV000145293	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496924	SCV000587454	likely pathogenic	Hereditary breast ovarian cancer syndrome	2015-12-17	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000031213	SCV001244020	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
deCODE genetics, Amgen	RCV000031213	SCV004022171	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-21	no assertion criteria provided	research	The variant NM_007294.4:c.5074G>A (chr17:43067608) in BRCA1 was detected in 26 heterozygotes out of 58K WGS Icelanders (MAF= 0,022%). Following imputation in a set of 166K Icelanders (70 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 20.57, P= 8.44e-16) and ovarian cancer using 907 cases and 299709 controls (OR= 29.05, P= 2.67e-10). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PS4, PP1, PP3, PP5_Strong) this variant classifies as pathogenic.
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332088	SCV004040520	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
Department of Medical and Surgical Sciences, University of Bologna	RCV000031213	SCV004228368	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	PS3(Strong)+PM2(Supporting)+PP3(Supporting)+PP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)