Submissions for variant NM_000059.4(BRCA2):c.9647T>C (p.Leu3216Pro)

gnomAD frequency: 0.00001  dbSNP: rs431825377

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164007	SCV000214611	likely benign	Hereditary cancer-predisposing syndrome	2018-01-31	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460198	SCV000549489	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3216 of the BRCA2 protein (p.Leu3216Pro). This variant is present in population databases (rs431825377, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 96885). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000164007	SCV000910004	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 3216 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with a segregation likelihood ratio for pathogenicity of 0.942 (PMID: 31131967). This variant has been identified in 2/282734 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004804096	SCV004846212	uncertain significance	BRCA2-related cancer predisposition	2024-06-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 3216 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with a segregation likelihood ratio for pathogenicity of 0.942 (PMID: 31131967). This variant has been identified in 2/282734 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998220	SCV005625358	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	The BRCA2 c.9647T>C (p.Leu3216Pro) variant has been reported in an individual with a personal and/or family history of hereditary cancer (PMID: 31853058 (2020)). This variant was reported as a variant of uncertain significance in a multifactorial likelihood study (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.0000071 (2/282734 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000083006	SCV000115080	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-08-15	no assertion criteria provided	clinical testing