Submissions for variant NM_000059.4(BRCA2):c.8027T>C (p.Met2676Thr)

gnomAD frequency: 0.00002  dbSNP: rs80359038

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084534	SCV000073404	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129443	SCV000184213	likely benign	Hereditary cancer-predisposing syndrome	2018-11-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000045391	SCV000210665	likely benign	not provided	2019-07-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21990134, 23108138, 24323938, 20104584, 18824701, 19043619, 31131967, 29394989, 29884841)
Counsyl	RCV000031718	SCV000488630	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045391	SCV000600778	likely benign	not provided	2018-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129443	SCV000903868	benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212268	SCV001737788	likely benign	not specified	2021-06-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8027T>C (p.Met2676Thr) 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 allele was found at a frequency of 1.6e-05 in 251108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8027T>C has been reported in the recent literature to have a benign HDR (homology directed repair) activity score of 5.66 (95% CI 4.86-6.57), also citing other studies such as Ikegami_2020 reporting a fClass1 (neutral) outcome utilizing BRCA2-deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors (Olaparib, Niraparib, Rucaparib, CBDCA) and an ACMG categorization of BS3, BP4 for a final classification of likely benign (Richardson_2021). This is further supported by Lindor_2012 reporting a class 2 (neutral) outcome based on multifactorial data and the ClinGen SVI criteria that now recognize ACMG BS3 criterion as sufficient evidence for a likely benign outcome (Tavtigian_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant with a predomiant consensus supporting a as benign (n=1)/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031718	SCV000054325	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-02-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031718	SCV000147251	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353755	SCV000592172	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Met2676Thr variant was identified in 2 of 4410 proband chromosomes (frequency 0.0005) from individuals with breast cancer (Borg 2010, Spearman 2008). The variant was also identified in dbSNP (ID: rs80359038) “With unknown allele” and LOVD. The p.Met2676Thr residue is not conserved in mammals and lower organisms, and the variant amino acid Threonine (Thr) is present in chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Two functional assays found the variant to be competent at homology-directed repair (Guidugli 2013, Karchin 2008), and three in silico studies predicted this variant to be likely nonpathogenic or neutral (Guidugli 2013, Karchin 2008, Lindor 2012). One histology-based predictive study was inconclusive, but the results for this variant were limited to one tumour specimen (Spearman 2008). 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 unknown significance.
BRCAlab, Lund University	RCV000031718	SCV004243799	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing