Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000131694 | SCV000186730 | likely benign | Hereditary cancer-predisposing syndrome | 2018-05-21 | 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. |
Gene |
RCV000589110 | SCV000512292 | likely benign | not provided | 2020-01-20 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 22753008, 21990134, 24728327, 18824701, 18779604, 31131967) |
Labcorp Genetics |
RCV001080309 | SCV000560220 | likely benign | Hereditary breast ovarian cancer syndrome | 2024-01-19 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000120271 | SCV000602705 | likely benign | not specified | 2016-11-15 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000131694 | SCV000911191 | benign | Hereditary cancer-predisposing syndrome | 2016-01-19 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000589110 | SCV001133519 | likely benign | not provided | 2022-08-30 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000120271 | SCV001338500 | likely benign | not specified | 2024-03-12 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.2207A>C (p.Glu736Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250714 control chromosomes (gnomAD v2, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2207A>C has been reported in the literature in an individual with an unspecified cancer diagnosis without evidence of cosegregation (Kurian_2008), and also, in a breast cancer tumor where it was interpreted as neutral by the authors (Spearman_2008). A publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of likely benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of breast tumor pathology, co-occurrence, family history and bioinformatic predictions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 29580235, 18779604, 21990134, 22753008, 31131967, 18824701). ClinVar contains an entry for this variant (Variation ID: 37455). Based on the evidence outlined above, the variant was classified as likely benign. |
Sharing Clinical Reports Project |
RCV000031036 | SCV000053630 | benign | Breast-ovarian cancer, familial, susceptibility to, 1 | 2012-02-01 | no assertion criteria provided | clinical testing | |
ITMI | RCV000120271 | SCV000084423 | not provided | not specified | 2013-09-19 | no assertion provided | reference population | |
Department of Pathology and Laboratory Medicine, |
RCV001357499 | SCV001552985 | likely benign | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA1 p.Glu736Ala variant was identified in the literature and classified using a multifactorial probability based model as likely benign, however the frequency of this variant in an affected population was not provided (Lindor_2012_21990134). The variant was also identified in dbSNP (ID: rs397507196) as “With Likely benign allele”, ClinVar (as likely benign by Ambry, GeneDx, Invitae, and ARUP, and as benign by SCRP), Clinvitae (4x), GeneInsight-COGR, LOVD 3.0 (2x), ARUP Laboratories (as likely benign) databases. The variant was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 30964 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 1 of 1620 chromosomes (freq: 0.000617), while the variant was not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, European (Finnish) and South Asian populations. The p.Glu736 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |