Submissions for variant NM_007294.4(BRCA1):c.5068A>C (p.Lys1690Gln)

gnomAD frequency: 0.00002  dbSNP: rs397507239

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225765	SCV000076769	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130370	SCV000185224	likely benign	Hereditary cancer-predisposing syndrome	2019-09-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000656791	SCV000210195	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: conflicting homology-directed repair ability, defective protein instability, but normal nuclear localization and classified as functional by a saturation genome editing survival assay (PMID: 26689913, 30209399, 30257991); Observed in multiple individuals with breast or other cancers (PMID: 15365993, 18006916, 26221963, 28111427, 28364669, 31825140, 35205313); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5187A>C; This variant is associated with the following publications: (PMID: 24772314, 28111427, 15365993, 26689913, 28664449, 28364669, 18006916, 21147198, 27257965, 26221963, 22333603, 30257991, 30209399, 30702160, 31470354, 31825140, 32467295, 33087888, 32803532, 29263802, 35205313, 36243179, 34621001, 31131967, 25348405)
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240688	SCV000265892	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000130370	SCV000683245	likely benign	Hereditary cancer-predisposing syndrome	2021-04-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765357	SCV000896622	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048756	SCV000918738	likely benign	not specified	2021-04-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5068A>C (p.Lys1690Gln) 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 benign effect of the variant on protein function. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Cline_2019). The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5068A>C, has been reported in the literature in individuals affected with breast and/or ovarian Cancer, predominantly of Asian origin (example, Ang_2007, Lang_2017, Li_2017, Lu_2015, Park_2017, Ryu_2017, Seo_2004, Wong_2016, Zhong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported (BRCA2 c.9294C>G, p.Y3098X, Wong_2016), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (example, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). At-least two submitters have re-classified this variant as likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000048756	SCV001160223	uncertain significance	not specified	2019-01-15	criteria provided, single submitter	clinical testing	The BRCA1 c.5068A>C; p.Lys1690Gln variant (rs397507239) variant is published in the medical literature in individuals with breast cancer (Ang 2007, Seo 2004, Li 2017). However, the variant has also been shown to functionally replace the wild type protein in a haploid cell culture model, indicating it is not deleterious (Findlay 2018). The variant is reported as a variant of uncertain significance by several sources and as likely benign by one source in the ClinVar database (Variation ID: 55370) and with an overall allele frequency of 0.003% (9/282724 alleles) in the Genome Aggregation Database. The lysine at this position is conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the variant is uncertain at this time. References: Ang P et al. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2276-84. Findlay GM et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct;562(7726):217-222. Li G et al. Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing. J Cancer Res Clin Oncol. 2017 Oct;143(10):2011-2024. Seo JH et al. BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat. 2004 Oct;24(4):350.
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV000225765	SCV001430335	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130370	SCV002537805	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656791	SCV004219438	uncertain significance	not provided	2023-08-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 15365993 (2004), 18006916 (2007), 29263802 (2016), 30287823 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1), breast and/or ovarian cancer (PMID: 28364669 (2017), 35205313 (2022)), and in unaffected individuals (PMID: 30287823 (2018), 32467295 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). The effect of this variant on protein function is conflicting. Two functional studies reported this variant was functionally normal in a homology-directed DNA repair assay (PMID: 26689913 (2015)), and a saturation genome editing assay (PMID: 30209399 (2018)). However, another functional study reported this variant was defective in homology-directed DNA repair and was mostly insoluble in an E.coli solubility assay (PMID: 30257991 (2018)). The frequency of this variant in the general population, 0.00045 (9/19948 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048756	SCV005090335	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077592	SCV000109395	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353418	SCV000591566	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Lys1690Gln variant was identified in 11 of 23576 proband chromosomes (frequency: 0.0005) from Asian individuals or families with breast and/or ovarian cancer and was present in 12 of 22482 control chromosomes (frequency: 0.0005) from healthy individuals (Momozawa 2018, Bhaskaran 2019, Ang 2007). The variant was also identified in dbSNP (ID: rs397507239) as "With Pathogenic, Uncertain significance allele", however it is noted that there is an alternate variant resulting in a stop codon at this position to which the pathogenic classification likely refers, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Color, Invitae and 3 other submitters; and as likely benign by SCRP), LOVD 3.0 (4 entries), UMD-LSDB (1 entry). The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 8 of 277098 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 8 of 18864 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. In a homology-directed repair assay this variant was shown to have activity comparable to wild type, though insufficient data was available to determine if the finding was statistically significant (Lu 2015). Protein sequence analysis suggests that Lys1690 plays a role in conjugation with small ubiquitin-like modifiers (SUMO) within the BRCT domain though the authors acknowledge that the exact site of conjugation remains unclear (Vialter 2011). The p.Lys1690 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Brotman Baty Institute, University of Washington	RCV000077592	SCV001242037	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro