17-43063930-C-T
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5096G>A(p.Arg1699Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699G) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.5096G>A | p.Arg1699Gln | missense_variant | Exon 17 of 23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5096G>A | p.Arg1699Gln | missense_variant | Exon 17 of 23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152020Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251262 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727212 show subpopulations
Age Distribution
GnomAD4 genome 0.0000132 AC: 2AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74246 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:15
Multifactorial studies suggest this variant is associated with breast and ovarian cancer; however, these risks appear to be lower than typical BRCA1 pathogenic variants in multiple studies (PMID: 16489001, 21990134, 22889855, 28490613, 28283652); The ENIGMA consortium has proposed modified variant-specific breast and ovarian cancer management recommendations (PMID: 28490613); Published functional studies are conflicting with regards to transcriptional activation, phosphopeptide binding activity, and homology-directed repair activity (PMID: 30458859, 28781887, 30257991, 20516115, 14534301, 18036263); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5215G>A; This variant is associated with the following publications: (PMID: 25639900, 25980754, 24675953, 25652403, 24695549, 24845084, 25556971, 25085752, 15235020, 16489001, 12827452, 16280041, 15172985, 15133503, 20378548, 22505045, 11157798, 25452441, 28400480, 29192238, 28888541, 11504767, 32980694, 32211327, 38167124, 12237282, 29922827, 22889855, 25782689, 24323938, 18036263, 21990134, 21447777, 21702907, 23231788, 23867111, 20455026, 21473589, 15290653, 19563646, 24504028, 17305420, 26777316, 19200354, 15133502, 16528612, 14534301, 26350514, 26727311, 27495310, 27099641, 26987529, 27741520, 28283652, 28398198, 28758972, 29346284, 22843421, 24728189, 28866612, 16683254, 29486991, 30458859, 30287823, 30078507, 30765603, 30612635, 30257991, 28781887, 20516115, 28490613, 12237281, 14615451, 14966099, 18042939, 22516946, 22811390, 25348405, 31347298, 31447099, 31263571, 32123317, 33309985, 32719484, 32710294, 33087888, 30787465, 34308104, 30130155, 35264596, 33804961, 34697415, 35464868, 35665744, 34663891, 35918668, 34981296, 35957908, 35534704, 34284872, 36243179, 29053726, 34887416, 33471991) -
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PP3, PP5, PM3_supporting, PS3, PS4 -
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The BRCA1 c.5096G>A (p.Arg1699Gln) variant has been reported in the published literature in multiple individuals with breast or ovarian cancer (PMIDs: 35918668 (2022), 26350514 (2015), 25452441 (2015), 22034289 (2012), 20455026 (2010), 12827452 (2003), 11504767 (2001)). However, this variant is reported as being associated with reduced penetrance, relative to other BRCA1 pathogenic variants (PMIDs: 31347298 (2019), 28490613 (2017), 28283652 (2017), 26777316 (2016), 26430151 (2015), 25085762 (2014), 22889855 (2012)). In general, functional studies have shown that this variant causes a reduction in BRCA1 protein activity (PMIDs: 28781887 (2016), 23867111 (2013), 21946536 (2011), 20516115 (2010), 21473589 (2011), 17308087 (2007), 11157798 (2001)). The frequency of this variant in the general population, 0.000053 (6/113618 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as a BRCA1 pathogenic variant with reduced penetrance, relative to other BRCA1 pathogenic variants. -
The BRCA1 c.5096G>A; p.Arg1699Gln variant (rs41293459), also known as 5215G>A, is reported in the literature in multiple individuals affected with breast or ovarian cancer (Couch 2015, Cunningham 2014, Rostagno 2003, Song 2014), but with reduced penetrance and an intermediate cancer risk compared to other pathogenic BRCA1 variants (Moghadasi 2018, Spurdle 2012). Functional analyses of the variant protein show conflicting results, with significant reductions in transcriptional activation (Lovelock 2007) and protein interactions (Coquelle 2011), but retention of an intermediate level of homologous recombination activity (Bouwman 2013), altogether suggestive of a hypomorphic and damaging effect. This variant is classified as pathogenic by an expert panel in ClinVar (Variation ID: 37636). It is only found on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.785). Additionally, another variant at this codon (c.5095C>T; p.Arg1699Trp) has been reported in individuals with breast or ovarian cancer and is considered pathogenic (Song 2014, Spurdle 2012). Based on available information, this variant is considered to be likely pathogenic with reduced penetrance and an intermediate risk for breast and ovarian cancer. References: Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov 2013 3(10):1142-55. PMID: 23867111. Coquelle N et al. Impact of BRCA1 BRCT domain missense substitutions on phosphopeptide recognition. Biochemistry 2011 50(21):4579-89. PMID: 21473589. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. PMID: 25452441. Cunningham JM et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 Feb 7;4:4026. PMID: 24504028. Lovelock P et al. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res 2007 9(6):R82. PMID: 18036263. Moghadasi S et al. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet. 2018 Jan;55(1):15-20. PMID: 28490613. Rostagno P et al. A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer. J Hum Genet. 2003;48(7):362-6. PMID: 12827452. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9. PMID: 24728189. Spurdle A et al. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J Med Genet 2012 49(8):525-32. PMID: 22889855. -
BRCA1: PS4, PM2, PM5, PS3:Moderate -
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This is a single base pair change replacing arginine by glutamine at amino acid position 1699 of the BRCA1 protein. This position is highly conserved among species and there is a small physiochemical difference between arginine and glutamine (Grantham Score 43). This missense change affects the highly conserved arginine 1699 residue within the BRCT-N domain (PMID: 22843421, 11157798).This variant is present in population databases (rs41293459, <0.01%). This variant is also known as 5215G>A in the literature and it has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11504767, 12827452, 16683254, 24728189). The mutation database Clinvar contains entries for this variant (Variation ID: 37636). Experimental studies have shown that this missense change can disrupt several functional activities of the BRCA1 protein, including transactivation (PMID: 18036263, 17308087, 11157798), phosphopeptide binding (PMID: 21473589, 15133503, 15133502), and nuclear foci formation (PMID: 18036263). However, this variant generally exhibits reduced or intermediate BRCA1 protein function. Modified segregation analysis of 30 families carrying the Arg1699Gln variant has shown that it has reduced penetrance compared with the average pathogenic, truncating BRCA1 variant. In addition, algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the BRCA1 protein. -
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Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:13Uncertain:1
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The c.5096G>A (p.Arg1699Gln) variant has been reported in multiple patients with breast and/or ovarian cancer [PMID 12827452, 24504028, 25782689]. Several functional in vitro assays showed ambiguous results: the p.Arg1699Gln showed intermediate deleterious effects but not to the extend of a well -characterized pathogenic variant [PMID 22889855, 23867111, 21473589]. Additionally, this variant showed a reduced penetrance in a study [PMID 22889855] and the risk for breast or ovarian cancer was reduced to 24 % by age 70. Additional changes affecting the same amino acid position (p.Arg1699Arg, p.Arg1699Leu, p.Arg1699Trp) have also been reported in patients with breast and/or ovarian cancer. This variant was reported in 3 heterozygous individuals in ExAC (http://exac.broadinstitute.org/variant/17-41215947-C-T). This variant is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Arg1699Gln change to be deleterious. This variant thus classified as likely pathogenic. -
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This variant has been shown to impact function (PMID:18036263, 23867111, 30257991, 30765603, 11157798). A genetic study (PMID:22889855) reported it to be associated with reduced risk compared to another pathogenic missense substitution variant at the same residue (BRCA1 c.5095C>T p.(Arg1699Trp)). A subsequent larger genetic study including 129 families (PMID:28490613) reported HRs of 2.83 for breast cancer and 5.83 for ovarian cancer risk, and estimated the cumulative risk to age 70 to be 20% for breast cancer and 6% for ovarian cancer. This variant is considered pathogenic with reduced penetrance relative to the average BRCA1 truncating pathogenic variant. Management recommendations for this specific variant were published in 2017 (PMID:28490613). In line with a recent publication that provides guidance on reporting for reduced penetrance variants in cancer susceptibility genes (PMID:30962250), clinical management recommendations should consider knowledge of personal and family history of disease, and other known genetic and environmental risk factors, that together can strongly influence absolute risk for an individual. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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The c.5096G>A;p.(Arg1699Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37636; PMID: 28490613) -PS4. The variant is present at low allele frequencies population databases (rs41293459 – gnomAD 0.0002388%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 55396) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 22889855, 28490613) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic -
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PVS1; PM2_Supporting; PP1 -
Hereditary breast ovarian cancer syndrome Pathogenic:9Other:1
The p.Arg1699Gln variant in BRCA1 has been reported in >60 individuals with BRCA1-associated cancers and segregated with disease in multiple relatives from 30 families (Spurdle 2012, Shimelis 2017, Moghadasi 2018). This variant has been described as having reduced penetrance compared to other disease-causing variants: up to 24% risk of BRCA1-related cancer by age 70 (95% CI, 10% to 40%) for Arg1699Gln carriers vs. 58% (95% CI, 7% to 72%) for Arg1699Trp carriers vs. 4.6% risk for women in the general population (Spurdle 2012, Moghadasi 2018). It has been identified in 6/113618 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). While some studies have demonstrated impaired in vitro protein activity, others report that the variant performed similar to wild-type (Williams 2003, Lovelock 2007, Chang 2011). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as a low-penetrant pathogenic variant for autosomal dominant HBOC. ACMG/AMP criteria applied: PS4, PP1_Strong, PM5, PM2_Supporting, PP3, PS3_Supporting. -
Variant summary: BRCA1 c.5096G>A (p.Arg1699Gln) involves the alteration of a conserved nucleotide that results in a conservative amino acid change located in the first BRCT domain (IPR001357) that is involved in interactions with phosphorylated partner proteins (Petitalot 2018) and also, functions as a transcriptional activation domain (Langerud 2018). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 252122 control chromosomes (gnomAD and publications). c.5096G>A has been reported in the literature in multiple individuals/families affected with Hereditary Breast and Ovarian Cancer, and was also noted to cosegregate with the disease (Ricevuto 2001), though, in one family the variant was absent in an affected individual (Gomez Garcia 2009). Although the variant of interest was found to co-occur with another potentially pathogenic BRCA2 variant, c.631+4A>G, within a HBOC family, the authors indicated that both variants contributed to the family phenotype (Steffensen 2010). Co-occurrences with other pathogenic variant(s) have also been reported elsewhere (BRCA2 c.9026_9030delATCAT, p.Tyr3009fsX7 in the UMD database). One study reported the variant in compound heterozygosity with a known BRCA1 pathogenic variant (p.Cys61Gly) in a woman with breast cancer who showed mild Fanconi anemia (FA)-like features, with the authors concluding that the comparatively mild FA-like clinical phenotype presented was most likely due to incomplete impairment of BRCA1 function by the p.Arg1699Gln risk allele (Keupp_2019). Case-control studies concluded that the variant confers lower breast and ovarian cancer risk than a typical BRCA1 pathogenic variant (Spurdle 2012, Shimelis 2017, Moghadasi 2018), the cumulative risk of breast and ovarian cancer by age 70 years being 20% and 6%, respectively; the authors refer to the variant as an intermediate risk variant conferring risks lower than that of the average pathogenic variant (ENIGMA consortium, Moghadasi 2018). Multiple independent functional studies reporting this variant have demonstrated: 1. proper or reduced BRCT domain folding, 2. loss of phosphopeptide binding, 3. decreased or intermediate transcriptional activity of the mutant BRCA1 constructs expressed in mammalian cell lines, and 4. defective homology-directed DNA repair (HDR) capacity and nuclear foci formation in mammalian cells, but preserved wild-type centrosome amplification function (Vallon-Christersson 2001, Williams 2003, Williams 2004, Carvalho 2007, Lovelock 2007, Rowling 2010, Lee 2010, Petitalot 2018, Langerud 2018). Although it is not clear how all the results and conclusions drawn from these in-vitro studies are applicable to the mechanism and presentation of disease, the convergence of results obtained from multiple independent functional assays are supportive of a hypomorphic and damaging effect of this variant on the BRCA1 gene product. Eighteen ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The c.5096G>A (p.Arg1699Gln) variant has been reported in multiple patients with breast and/or ovarian cancer [PMID 12827452, 24504028, 25782689]. Several functional in vitro assays showed ambiguous results: the p.Arg1699Gln showed intermediate deleterious effects but not to the extend of a well -characterized pathogenic variant [PMID 22889855, 23867111, 21473589]. Additionally, this variant showed a reduced penetrance in a study [PMID 22889855] and the risk for breast or ovarian cancer was reduced to 24 % by age 70. Additional changes affecting the same amino acid position (p.Arg1699Arg, p.Arg1699Leu, p.Arg1699Trp) have also been reported in patients with breast and/or ovarian cancer. This variant was reported in 3 heterozygous individuals in ExAC (http://exac.broadinstitute.org/variant/17-41215947-C-T). This variant is conserved in mammals. Although not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Arg1699Gln change to be deleterious. This variant thus classified as likely pathogenic. -
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The missense variant NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln) causes the same amino acid change as a previously established pathogenic variant. The p.Arg1699Gln variant is observed in 6/113,618 (0.0053%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Arg1699Gln variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene BRCA1 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.32. The gene BRCA1 contains 246 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 17 variants within 6 amino acid positions of the variant p.Arg1699Gln have been shown to be pathogenic, while only 1 have been shown to be benign. The p.Arg1699Gln missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 1699 of BRCA1 is conserved in all mammalian species. The nucleotide c.5096 in BRCA1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1699 of the BRCA1 protein (p.Arg1699Gln). This variant is present in population databases (rs41293459, gnomAD 0.005%). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 11504767, 12827452, 16683254, 20455026, 24504028, 24728189, 25452441, 28490613). In a large family cohort study, including 67 families in which the probands carried the Arg1699Gln change, this variant was shown to segregate with breast and ovarian cancer (PMID: 22889855). This variant is also known as 5215G>A in the literature. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37636). Modified segregation analysis of 129 families carrying Arg1699Gln has shown that this variant confers intermediate risk for breast and ovarian cancer (PMID: 28490613). The risk of breast cancer by age 70 years is 20% when compared to 8% risk for women in the general population, versus 65% risk for carriers of an average pathogenic BRCA1 variant. The risk of ovarian cancer by age 70 years is 6% when compared to 1% risk for women in the general population, versus 39% risk for carriers of an average pathogenic BRCA1 variant. This missense change affects the highly conserved arginine 1699 residue within the BRCT-N domain (PMID: 22843421, 11157798). While the results are somewhat conflicting among the different reports, experimental studies have shown that this missense change can disrupt several functional activities of the BRCA1 protein, including transactivation (PMID: 18036263, 17308087, 11157798), phosphopeptide binding (PMID: 21473589, 15133503, 15133502), and nuclear foci formation (PMID: 18036263). However, this variant generally exhibits reduced or intermediate BRCA1 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the BRCA1 gene, it has been classified as Pathogenic (low penetrance). -
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Intermediate risk variant -
This variant is considered pathogenic with reduced penetrance relative to the average BRCA1 truncating pathogenic variant; According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30257991, 32546644, 30765603) (PS3 met)., PM3 (supporting pathogenic): 2 Punkte, Keupp 2019, comp het in Fall mit FA, PP3 (supporting pathogenic): BayesDEL:0.419574 , PP4 (supporting pathogenic): Combined LR Score 25.495 -
Hereditary cancer-predisposing syndrome Pathogenic:3
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This missense variant replaces arginine with glutamine at codon 1699 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant impairs BRCA1 function in transcription activation, cisplatin and PARP inhibitor sensitivity, and homology-directed DNA repair assays (PMID: 11157798, 30458859, 30765603, 32546644). This variant has been detected in over 20 individuals and families affected with breast and ovarian cancer (PMID: 11157798, 11410501, 11504767, 12827452, 24504028, 24728189, 25452441, 27495310, 28283652, 29486991, 30287823, 33471991, 35039564, 37563628). This variant has been reported to have reduced penetrance, conferring intermediate risk for breast and ovarian cancer based on case-control studies, carrier family history, segregation and functional studies (PMID: 16489001, 22889855, 28283652, 28490613, 39488595). A study of 129 families carrying this variant have shown cumulative risks for this variant by age 70 years are about 20% (95% CI 13% to 32%) for breast cancer and 6% (95% CI 3% to 25%) for ovarian cancer, which are between that for BRCA1 truncating variants and the general population (PMID: 28490613). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 25.495 from log(LR)=1.406 for 16 carriers (PMID: 31853058). This variant also has been reported in an individual affected with Fanconi anemia with a pathogenic BRCA1 missense variant p.Cys61Gly in trans (PMID: 38146508). This variant has been identified in 6/251262 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance. -
The p.R1699Q moderate risk mutation (also known as c.5096G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5096. The arginine at codon 1699 is replaced by glutamine, an amino acid with highly similar properties. In one functional study, the p.R1699Q alteration was shown to destabilize the BRCT domain of the BRCA1 protein and demonstrated reduced, but not abolished, BRCA1 activity (Lovelock PK et al. Breast Cancer Res. 2007;9:R82). In another functional study analyzing protein expression levels in transfected mouse embryonic stem cells, the p.R1699Q alteration showed an intermediate effect in a cisplatin sensitivity assay and a deleterious effect in a PARP inhibitor assay. This alteration also showed an intermediate level of homologous repair activity compared to wild-type. Based on these findings, the authors noted that the p.R1699Q alteration would likely lead to an intermediate risk for HBOC (Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55). In a study comparing phenotype and segregation data from 68 p.R1699Q families to 34 pathogenic BRCA1 p.R1699W kindreds and 243 BRCA1 mutation-free families, results strongly supported p.R1699Q as an intermediate risk allele, conferring an estimated 24% (95% CI: 10-40%) risk of female breast or ovarian cancer by age 70 (Spurdle AB et al. J. Med. Genet. 2012 Aug;49:525-32). These risks were further supported by the ENIGMA consortium which calculated a 20% and 6% increased risk of breast and ovarian cancer, respectively, by age 70 (Moghadasi S et al. J. Med. Genet. 2018 Jan;55:15-20). This mutation has also been detected in trans with BRCA1 c.181T>G (p.C61G) in an individual diagnosed with breast cancer at age 30 years and a mild Fanconi anemia phenotype lacking chromosome fragility (Keupp K et al. Mol Genet Genomic Med 2019 09;7(9):e863). Of note, this alteration is also designated as 5215G>A in published literature. Based on the available evidence, this alteration is classified as a moderate risk mutation that may not be associated with classic HBOC, but rather leads to increased risk of developing a BRCA1-related cancer. Clinical correlation is advised. -
Familial cancer of breast Pathogenic:2
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Criteria applied: PS3,PM3_SUP,PP3,PP4 -
Breast and/or ovarian cancer Pathogenic:1Uncertain:1
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BRCA1-related cancer predisposition Pathogenic:1
This missense variant replaces arginine with glutamine at codon 1699 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant partially to fully impacts BRCA1 function in homology-directed repair and cisplatin sensitivity assays (PMID: 23867111, 28398198) and transcription activation and phosphopeptide binding assays (PMID: 11157798, 15133502, 15133503, 18036263, 20516115). This variant has been detected in over 20 individuals and families affected with breast and ovarian cancer (PMID: 11157798, 11410501, 11504767, 12827452, 24504028, 24728189, 25452441, 27495310, 28283652, 29486991, 30287823, 33471991, 35039564). This variant has been reported to be of reduced penetrance, conferring intermediate risk for breast and ovarian cancer based on case-control studies, analysis of carrier family history, and functional studies (PMID: 16489001, 22889855, 28283652, 28490613). In particular, a study of 129 families carrying this variant have shown cumulative risks for this variant by age 70 years are about 20% (95% CI 13% to 32%) for breast cancer and 6% (95% CI 3% to 25%) for ovarian cancer. These risks are lower than for high-risk BRCA1 truncating variants and higher than for the general population (PMID: 28490613). This variant has been identified in 6/251262 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 8 unaffected individuals (PMID: 33471991). A different variant affecting the same codon, p.Arg1699Trp, is considered to be disease-causing (ClinVar variation ID: 55396), suggesting that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
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Gastric cancer Pathogenic:1
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BRCA1-related disorder Pathogenic:1
The BRCA1 c.5096G>A variant is predicted to result in the amino acid substitution p.Arg1699Gln. This variant has been reported in a large number patients and families with breast and ovarian cancer (Rostagno et al. 2003. PubMed ID: 12827452; Spurdle et al. 2012. PubMed ID: 22889855; Moghadasi et al. 2017. PubMed ID: 28490613) and at least in one individual with suspected Lynch syndrome (Table S1, Yurgelun et al. 2015. PubMed ID: 25980754). A recent study of 129 families with this variant estimated cumulative (by age 70) risks of 20% and 6% for breast and ovarian cancer, respectively (Moghadasi et al. 2017. PubMed ID: 28490613). Functional studies suggest that this variant may impair protein function (Lovelock et al. 2007. PubMed ID: 18036263; Lee et al. 2010. PubMed ID: 20516115; Bouwman et al. 2013. PubMed ID: 23867111). This variant is reported in 0.0053% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37636/). This variant is interpreted as likely pathogenic. -
Ovarian neoplasm Pathogenic:1
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Fanconi anemia, complementation group S Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at