Submissions for variant NM_000465.4(BARD1):c.1212C>G (p.Tyr404Ter)

gnomAD frequency: 0.00002  dbSNP: rs587782681

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132107	SCV000187172	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The p.Y404* pathogenic mutation (also known as c.1212C>G), located in coding exon 4 of the BARD1 gene, results from a C to G substitution at nucleotide position 1212. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This pathogenic mutation has been reported in multiple individuals diagnosed with ovarian cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000195626	SCV000253839	pathogenic	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr404*) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). This variant is present in population databases (rs587782681, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with a family history of ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 142734). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413940	SCV000490425	pathogenic	not provided	2023-09-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast or ovarian cancer (Ramus et al., 2015; Lilyquist et al., 2017; Arvai et al., 2019; Lim et al., 2022); This variant is associated with the following publications: (PMID: 26315354, 31341520, 32832836, 30322717, 29790872, 31589614, 29700634, 28888541, 33804961, 36315097)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000195626	SCV000584071	pathogenic	Familial cancer of breast	2016-10-13	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000132107	SCV000688103	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the BARD1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in at least one individual affected with ovarian cancer (PMID: 30322717, 31341520). This variant has been identified in 3/282382 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mendelics	RCV000195626	SCV000837969	pathogenic	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000195626	SCV000893573	pathogenic	Familial cancer of breast	2022-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201181	SCV001372239	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-09	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1212C>G (p.Tyr404X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250984 control chromosomes (gnomAD). c.1212C>G has been reported in the literature in individuals with personal and/or family history of breast or ovarian cancer (e.g. Carter_2018, Kaur_2018, Ramus_2015). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000195626	SCV004044101	pathogenic	Familial cancer of breast	2023-05-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000195626	SCV004214965	pathogenic	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945152	SCV004776206	pathogenic	BARD1-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	The BARD1 c.1212C>G variant is predicted to result in premature protein termination (p.Tyr404*). This variant has been reported in at least five individuals (including one sibling pair) with a personal and/or family history of breast and ovarian cancer (Ramus et al. 2015. PubMed ID: 26315354; Lilyquist et al. 2017. PubMed ID: 28888541; Kaur et al. 2018. PubMed ID: 29700634; Carter et al. 2018. PubMed ID: 30322717). This variant has also been reported in an individual with prostate cancer (Matejcic et al. 2020. PubMed ID: 32832836). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/142734/). Nonsense variants in BARD1 are expected to be pathogenic. This variant is interpreted as pathogenic.