ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3448C>T (p.Pro1150Ser) (rs80357272)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112099 SCV001161572 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02;, AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02;, AND minor allele frequency 0.00119 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001080313 SCV000076213 benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131184 SCV000186131 likely benign Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Subpopulation frequency in support of benign classification
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240742 SCV000265876 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
GeneDx RCV000587116 SCV000568411 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3448C>T at the cDNA level, p.Pro1150Ser (P1150S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant has been previously published as BRCA1 3567C>T. This variant was observed in individuals with breast cancer, but was also seen in controls (Katagiri 1996, Tang 1999, Belogianni 2004, Jang 2012, Yoon 2016, Zhong 2016, Li 2017, Ryu 2017). A homologous-directed repair assay demonstrated that this variant results in homologous recombination activity similar to the wildtype protein (Lu 2015). BRCA1 Pro1150Ser was observed at an allele frequency of 0.095% (18/18866) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1150Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro1150Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587116 SCV000699033 likely benign not provided 2016-03-17 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000240742 SCV000803955 uncertain significance Breast neoplasm 2017-06-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131184 SCV000902976 likely benign Hereditary cancer-predisposing syndrome 2015-12-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587116 SCV001133552 benign not provided 2019-03-26 criteria provided, single submitter clinical testing
Mendelics RCV000112099 SCV001140553 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112099 SCV000144767 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000483961 SCV000587311 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000112099 SCV001549557 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Pro1150Ser variant was identified in 13 of 4830 proband chromosomes (frequency: 0.003) from Chinese and Korean individuals or families with breast cancer, and in 3 of 1892 control chromosomes (frequency: 0.002) from healthy individuals (Tang 1999, Li 2017 , Jang 2012, Suter 2004, Yang 2017, Yoon 2016). The variant was also identified in dbSNP (ID: rs80357272) as “With other allele”, in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: uncertain significance by Ambry Genetics, CHEO Genetics Diagnostic Laboratory, Laboratory of Molecular Diagnosis of Cancer, GeneDx, and BIC, and likely benign by Invitae and Laboratory Corporation of America), Clinvitae (5x), LOVD 3.0 (1x), BIC Database (5x), with unknown clinical importance, classification pending), and Zhejiang University Database (1x). The variant was identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic BRCA2 variant (c.3109C>T, p.Gln1037X); in addition, the variant was identified in UMD-LSDB 2x as 3-UV, co-occurring with a pathogenic BRCA1 variant (c.3181delA, p.Ile1061X), increasing the likelihood that the variant does not have clinical significance. The variant was not identified in Cosmic, MutDB, and ARUP Laboratories. The variant was identified in control databases in 18 of 276992 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 18 of 18866 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Pro1150 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.

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