Submissions for variant NM_000465.4(BARD1):c.1098_1099delinsAC (p.Ser367Pro)

dbSNP: rs1064794052

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486835	SCV000567679	uncertain significance	not specified	2015-08-19	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.1098_1099delTTinsAC at the cDNA level, p.Ser367Pro (S367P) at the protein level, and results in the change of a Serine to a Proline (TCA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Ser367Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Ser367Pro occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BARD1 Ser367Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851170	SCV002134216	uncertain significance	Familial cancer of breast	2023-07-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 419699). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 367 of the BARD1 protein (p.Ser367Pro). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BARD1-related conditions.
Color Diagnostics, LLC DBA Color Health	RCV005402928	SCV006063391	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 367 of the BARD1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BARD1-related disorders in the literature. This variant has not been identified 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356832	SCV001552103	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Ser367Pro variant was not identified in the literature nor was it identified in the dbSNP, Cosmic, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in ClinVar (1x, as uncertain significance by GeneDx), Clinvitae (1x, as uncertain significance, by ClinVar). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. This variant is an in-frame deletion insertion resulting in the removal of a serine (ser) residue at codon 367; the impact of this alteration on BARD1 protein function is not known. The p.Ser367 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.